MBO(N)D - esi.umontreal.ca · Insight II MBO(N)D March 2000 Accelrys 9685 Scranton Road San Diego, CA 92121-3752 858/458-9990 Fax: 858/458-0136

Insight IIMBO(N)D

March 2000

Accelrys9685 Scranton Road

San Diego, CA 92121-3752

858/458-9990 Fax: 858/458-0136

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MBO(N)D v

Table of Contents

1. Introduction 9

What Is MBO(N)D? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

MBO(N)D—The Insight and standalone modes of operation. . . 10

Starting MBO(N)D. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

Using this guide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

Additional information. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

Notes on command names . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

2. Theory and Implementation 15

The MBO(N)D approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15Multigranularity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15Computational speedups . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

Substructured molecular dynamics . . . . . . . . . . . . . . . . . . . . . . . 17Multibody dynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17Substructuring the macromolecular model . . . . . . . . . . . . . . 20

Generating component modes for flexible bodies . . . . . . . . . . . . 20System modes versus component modes . . . . . . . . . . . . . . . 21

Temperature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24Precautions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24How temperature is controlled . . . . . . . . . . . . . . . . . . . . . . . 24

Constraints during dynamics simulations . . . . . . . . . . . . . . . . . . 25

Integration algorithms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

Brief description of the MBOND/CHARMm interface . . . . . . . . 27

3. General Methodology 29

Substructuring strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29Molecular domains . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29Alpha helices and pseudodihedral angle analysis . . . . . . . . . 30Beta sheets and interpeptide plane angle analysis . . . . . . . . 31Loops and turns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32Sidechain substructuring . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32Lessons learned . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33Other analytical methods to aid substructuring. . . . . . . . . . . 34

Analysis of B-factor data . . . . . . . . . . . . . . . . . . . . . . . . 34

vi MBO(N)D

Difference between two experimental conformations. . .34Secondary structure calculation. . . . . . . . . . . . . . . . . . . .35

Substructured dynamics and topological loops . . . . . . . . . . .35

Choice of reference coordinates and selection of modes. . . . . . . .36

Initial coordinates and velocities . . . . . . . . . . . . . . . . . . . . . . . . . .37

Stages and duration of dynamics simulation . . . . . . . . . . . . . . . . .37

Dynamics output . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .39

4. Methodology—Insight 41

Preliminary tasks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .41

Preparing the model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .43Minimizing the model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .43Substructuring. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .43

Example 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .46Example 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .47Example 3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .47

Generating modes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .49Loading modes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .50Animating modes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .50

Setting up the MBO(N)D simulation run . . . . . . . . . . . . . . . . . . .51Specifying how to handle nonbond interactions. . . . . . . . . . .51The Miscellaneous Mean Field Potential (MMFP) . . . . . . . .52Constant VELocity method (CVEL) . . . . . . . . . . . . . . . . . . .52Setting up the dynamics calculation . . . . . . . . . . . . . . . . . . . .52

Constant-temperature dynamics, equilibration stage . . .53Constant-temperaturedynamics,atomisticdata-collectionstage

53Constant-energy dynamics, data collection . . . . . . . . . . .54Output frequencies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .54Stream files . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .54

Setting up the parameter mode . . . . . . . . . . . . . . . . . . . . . . . .55MTS integrator . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .55Setting up the background job . . . . . . . . . . . . . . . . . . . . . . . .56

Running the MBO(N)D simulation . . . . . . . . . . . . . . . . . . . . . . . .58Submitting the MBO(N)D job . . . . . . . . . . . . . . . . . . . . . . . .58Monitoring a background job . . . . . . . . . . . . . . . . . . . . . . . . .59

5. Command Summary—Insight 61

Bodies pulldown . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .61

Modes pulldown . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .62

SetUp pulldown . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .63

MBOND_Run pulldown . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .63

Background_Job pulldown . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .63

MBO(N)D vii

6. Command Summary—Standalone Mode 65

MBO(N)D-specific keywords . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

MBO(N)D dynamics keywords . . . . . . . . . . . . . . . . . . . . . . . . . . 66

7. Methodology—Standalone Mode 67

Running an MBO(N)D simulation in standalone mode. . . . . . . . 67Input files required . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67General MBO(N)D procedure . . . . . . . . . . . . . . . . . . . . . . . 68General outline of command input file . . . . . . . . . . . . . . . . . 69

Specific commands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69

8. Tutorials 73

Introduction and overview of Pilot online tutorials . . . . . . . . . . . 73

A. References 75

B. File Formats 77

Input files . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77

MBO(N)D-specific files. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77

C. Miscellaneous 79

Technical notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79

Unsupported CHARMm facilities . . . . . . . . . . . . . . . . . . . . . . . . 80

D. Commands—Standalone Mode 81

Documentation format . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81

CHARMm command lines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81General format of MBO(N)D as single-line command . . . . 81General format of MBO(N)D command block. . . . . . . . . . . 82

Detailed command descriptions . . . . . . . . . . . . . . . . . . . . . . . . . . 83CVEL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83DYNAMICS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83GENERATE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85MBOND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87MODES. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89MTS integrator . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93SUBStructure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96

viii MBO(N)D

MBO(N)D 9

1 Introduction

What Is MBO(N)D?

Classical molecular dynamics, which treats each atom in a model as a threedegree-of-freedom particle, is severely limited for large models and longtime scales. This is due to the large number of degrees of freedom, as wellas the high-frequency content of the dynamics, which requires small inte-gration step sizes. With classical molecular dynamics, the size of the modelgenerally needs to be fewer than 25,000 atoms and the length of the simu-lation less than 100 ps. In addition, it is difficult to analyze the structure-function (collective atom architectures) relationships in the model.

Many large molecules are organized into aggregates of atoms that functioncollectively. Depending on the amount of motion considered, these aggre-gates can be residues, residue parts, alpha helices, beta sheets, modeldomains, or whole subunits. Because of these collective motions, it is pos-sible to approximate the motions of these aggregates by the motions ofequivalent rigid or flexible bodies. The MBO(N)D® (or MBOND®)approach allows a model to be substructured into a set of interconnectedrigid and flexible bodies and atomistic regions. The deformation of flexiblebodies is represented by a set of low-frequency component modes, whichallows the use of larger time steps in the simulation.

You can think of the MBO(N)D approach as a generalized way of con-straining a large computational model. It has become common practice toapply SHAKE or RATTLE constraints for atomistic simulations to elimi-nate the uninteresting high-frequency behavior due to bond-stretchingmotions. It is also possible to constrain bond angle bending, allowing onlytorsional degrees of freedom, to further eliminate high-frequency behaviorand allow larger time steps. The MBO(N)D approach extends these con-straints from two-atom (for bond lengths) and three-atom (for angles) con-straints to constraints involving many more atoms. The use of low-frequency component modes is equivalent to eliminating the uninterestinghigh-frequency behavior of the group of atoms that comprises the body.

10 MBO(N)D

1. Introduction

And the use of bodies means that arbitrarily large motions can be allowedat the bond connecting adjacent bodies, which is very important for allow-ing appropriate flexibilities in large models.

The MBO(N)D approach provides an intuitive modeling approach for sim-ulation of large biological and synthetic molecules and allows you to focuson the molecular substructures responsible for function. A substructureddescription of the model has many fewer degrees of freedom than an all-atom model (note that all atoms are still present and are used to determineforce terms). By substructuring, it is possible to reduce the degrees of free-dom computed from hundreds of thousands to tens or hundreds and toincrease the simulation time step from one femtosecond to tens or hundredsof femtoseconds.

Organizing large models into bodies not only improves the computationalefficiency but also allows a more simplified analysis of the collective atom(substructure)–function relationships.

Examples of molecular events whose study is enabled by this methodologyinclude:

© Docking.

© Conformational changes such as HIV flap movement and subunit shiftsin hemoglobin between oxy and deoxy states.

© Protein/polymer folding and diffusional conformational changes.

© Free energy changes.

Software developed in the 1980’s for solving large aerospace simulationproblems (Bodley et al. 1978) has been adapted to molecular systems byMoldyn (Turner et al. 1993) (and in turn adapted to the Insight environmentby MSI), to provide this atom aggregation (model substructuring) andbody-based simulation technique. The resulting simulation software iscalled MBO(N)D (multibody order-N dynamics).

MBO(N)D—The Insight and standalone modes ofoperation

MBO(N)D can be run as a standalone program or as an application withinthe Insight II graphical molecular modeling interface, which is availablefrom MSI under separate license.

Starting MBO(N)D

MBO(N)D 11

When used within the Insight interface, MBO(N)D is accessible as one ofits application modules. (For more information on the basic operations,procedures, and functionality of the Insight program, please refer to theInsight documentation.) The functionality in MBO(N)D is accessedthrough pulldowns that contain the commands to set up the input controlfile for a MBO(N)D job. The parameter block for each command providesyou with many useful defaults and preset strategies, all of which can be eas-ily modified, if necessary, for your particular calculation. References toatoms or residues can be typed in or can be specified by picking the appro-priate atom or residue in the displayed structure. You can then start the runwhile remaining in the Insight environment.

The MBOND module allows you to run the dynamics package MBO(N)Don a set of bodies that are defined within the module. You can generate orload various modes for each body and animate a particular mode for a body.Since MBO(N)D is interfaced to CHARMm, many of the CHARMm setupcommands are also available with defaults specific to MBO(N)D.

The parameter blocks in the Insight interface can also be used to prepareinput files for running MBO(N)D in the standalone mode. These input filescan be edited to develop more sophisticated computational strategies or forrepetitive calculations better suited to the automatic control of batchqueues.

When run as a standalone program outside the Insight environment,MBO(N)D uses a combined MBOND/CHARMm executable calledmbond.exe. In standalone mode, MBO(N)D has some capabilities that arenot accessible through the Insight interface, for example:

© More comprehensive reporting (status, print level).

© More control over various options.

Some additional features and flexibility are available through theCHARMm language interfaces.

Starting MBO(N)D

MBO(N)D can be invoked within the Insight program by selectingMBOND from the Module pulldown (i.e., the MSI logo). Several newpulldowns appear on the lower menu bar: Bodies, Modes, SetUp,Background_Job, Forcefield, and MBOND_Run. Most of the com-mands in these MBO(N)D pulldowns are actually used to set up the input

12 MBO(N)D

1. Introduction

file—MBO(N)D is not actually run until the MBOND_Run command isexecuted.

You can also set up and run MBO(N)D independent of the Insight interface.The standalone mode of operation is described in Chapter 7,Methodology—Standalone Mode.

Using this guide

This guide contains instructions for preparing input files, running jobs, andinterpreting output. In addition, it presents theoretical information onMBO(N)D. The Introduction, Theory and Implementation, General Meth-odology, References, File Formats, and Miscellaneous chapters containbackground information that is relevant to both the Insight and standalonemodes of using MBO(N)D.

General Information Chapter 2, Theory and Implementation presents the theories upon whichthe functionalities of MBO(N)D are based. It is written mainly for the typ-ical scientist-user of MBO(N)D. This section also presents some informa-tion on how the functionalities are implemented. Chapter 3, GeneralMethodology presents the general procedure for using MBO(N)D, either inthe Insight environment or in the standalone mode.

Appendix A, References contains the scientific references cited in thisguide. The file formats are documented separately for the files used bymore than one program and in Appendix B, File Formats for files specificto MBO(N)D. Miscellaneous other information is contained in AppendixC, Miscellaneous.

Using MBO(N)D viaInsight interface

The Command Summary—Insight and Methodology—Insight chapterscontain information that is specific to using MBO(N)D in the Insight envi-ronment. Chapter 5, Command Summary—Insight briefly summarizes themain functions of each command. Chapter 4, Methodology—Insightexplains how to use MBO(N)D in the Insight mode.

Using MBO(N)D in stan-dalone mode

The Command Summary—Standalone Mode, Methodology—StandaloneMode, and Commands—Standalone Mode chapters contain informationthat is specific to using MBO(N)D in standalone mode. Chapter 6, Com-mand Summary—Standalone Mode briefly summarizes the main com-mands. Chapter 7, Methodology—Standalone Mode explains how to useMBO(N)D in standalone mode. Appendix D, Commands—StandaloneMode explains the standalone keywords in detail.

Additional information

MBO(N)D 13

Additional information

In addition to this MBO(N)D documentation set, additional on-line help isavailable and activated by clicking the help icon in the main Insight win-dow) or using the Help pulldown. Printouts can be obtained through thishelp utility.

Help can also be obtained during input preparation with CHARMm byaccessing the CHARMm documentation from MSI’s website:

http://www.msi.com/

Information pertaining specifically to the Insight interface and its defaultmodules is contained in the Insight documentation.

Technical information that is mainly of use to programmers and systemadministrators is contained in the System Guide. The Release Notesinclude information on new features.

To keep up with the latest research into substructuring and other develop-ments associated with this software, you should regularly check the MSIwebsite at http://www.msi.com/

Notes on command names

In referring to commands that are used when running MBO(N)D interac-tively through the Insight interface, this guide uses the format Pulldown/Command, since you must use the mouse to first select the pulldown,before the command name appears. Note, however, that if you enter com-mands in the command area near the bottom of the Insight window, thecommand names must be entered in the format Command Pulldown orCommand (whichever appears at the top of the equivalent parameterblock).

For conventions used in documenting the standalone commands, please seeAppendix D, Commands—Standalone Mode.

14 MBO(N)D

1. Introduction

MBO(N)D 15

2 Theory and Implementation

The MBO(N)D approach

The most important feature of MBO(N)D is that of substructuring. InMBO(N)D’s substructuring approach, groups of atoms are aggregated intorigid or flexible bodies. These bodies are allowed to undergo large motionsrelative to each other, but within each body the relative motions among theaggregated atoms is small and non-random (for flexible bodies) or nil (rigidbodies). Single atoms can be mixed with bodies of various sizes in regionswhere relative motion between atoms is expected to be large. For example,the alpha-helices and beta-sheets of proteins might be modeled as rigid orflexible bodies, while loop regions are modeled at the full atomistic level.This approach dramatically reduces the number of degrees of freedom inthe dynamics equations. Substructuring is a natural enabler of multigranu-larity simulations, where different regions of the molecule are modeled atvarying levels of fidelity (flexible/rigid bodies and/or atoms), depending ontheir importance to the particular event being studied.

Multigranularity

Flexible bodies MBO(N)D’s flexible bodies are modeled by a reduced set of componentmodes. The reduced set is generally selected from the lowest-frequencymodes, which correspond to the overall motions of the body. The high-fre-quency modes corresponding to local vibrations that are not important tothe event of interest can be eliminated.

Rigid bodies MBO(N)D’s rigid bodies are just special cases of flexible bodies, wherenone of the component modes are retained.

Particle bodies Particle bodies are bodies consisting of a single atom with only three trans-lational degrees of freedom. In other words, particle bodies are used whenno aggregation into larger bodies is appropriate or desirable and the atom-istic degrees of freedom are to be retained.

16 MBO(N)D

2. Theory and Implementation

Computational speedups

Longer time steps Elimination of high-frequency components is one of the key MBO(N)Dattributes that allows larger time steps to be taken during the moleculardynamics simulation, effecting a dramatic decrease in the number of stepsrequired to simulate long-duration molecular events. The highest frequencymotions place the effective limit as to how large the time step can be forsingle time scale simulations.

Multiple time scales The concept of multigranularity goes hand in hand with integrator imple-mentations that make use of multiple time scales in the physical system. Inthis way, the motion in regions that are modeled using particle bodies canbe integrated using shorter time steps, while the motion in regions that aremodeled as bodies (rigid or flexible) can be integrated using longer timesteps.

MBO(N)D allows the modeling of any molecular system as a combinationof atoms, rigid bodies, and flexible bodies. The motions and interactionsinvolving individually modeled atoms are expected to have high-frequencycontent, while those for bodies is expected to be of a lower-frequency con-tent. Even for conventional all-atom models, you can take advantage of theseparation of time scales that exists between fast interactions (such as bondstretching) and slow interactions (such as long-range electrostatics). ForMBO(N)D, the natural separation of time scales involves body size.Indeed, power spectra of the body-based forces, consisting of the net forcevector of the body, net torque vector of the body, and the modal force vec-tor, are dominated by low-frequency behavior.

MBO(N)D can handle up to five time scales, and the separation of timescales is determined by a simple criterion that is applied to each atom pairin the nonbond pair list. The criterion is used to sort the nonbond pair listinto several bins, for evaluation at user-specified or automatically deter-mined rates. The criterion is based on the following equation:

Eq. 1

where Mi is the interaction mass of the i-th atom (which is the mass of thebody if the atom belongs to a rigid body or is the mass of the atom itself ifit belongs to a flexible body or is a particle), and Co is a calibration factor.The distance-dependent interaction compliance factor, C(r), is introduced

T CoC r( )M1M2

M1 M2+---------------------=

Substructured molecular dynamics

MBO(N)D 17

to account for the dependence of the time scale of interaction on the dis-tance between two interacting atoms:

Eq. 2

given the parameters A and ro. A suitable choice of parameters for Eq. 1and Eq. 2 is described under MTS integrator.

For each interaction, MBO(N)D compares the value of Eq. 1 with the spec-ified time step ratios, to place the interaction pair into the appropriate bin.

The eigensolution process The eigensolution process needed to generate component modes is gener-ally more tractable for this substructured model than that required for nor-mal mode analysis because the mode shapes and frequencies are calculatedseparately for individual bodies, rather than for the entire system. It is com-putationally less expensive to compute eigensolutions of component bodieswithin a system than it is to compute the eigensolution of the entire system.


Multibody dynamics

The physical system undergoing analysis may be generally described as acluster of contiguous, flexible substructures (bodies) that comprise adynamical system such as a biopolymer. Member bodies of the moleculeare capable of undergoing large relative excursions such as those of flapsor loop regions. Bodies of the system may be interconnected by fixed orfree bond lengths. This type of multibody system is acted on by inertialforces (such as those due to centrifugal and Coriolis acceleration), as wellas by the usual forces derived from empirical potentials.

For further introduction to the multibody description of the physical sys-tem, consider an illustrative example, such as the system of bodies ofFigure 1, and let this example be the prototype for all subsequent discus-sion.

C r( )1 if r r0≤( )

A r r0–( ) 1+ if r r0>( )��

=

18 MBO(N)D


Figure 1 shows a topological configuration that includes five hinges andfour bodies (and thus one closed path). By convention, body 1 (which maybe any body of the system) is associated with hinge 1.

For each body of the system, there is a body-fixed, right-handed referenceframe, whose origin may be the body’s mass center or some atom in thebody. (A body’s elastic deformation is measured in its reference frame.)

A hinge is defined as a pair of points (normally coincident with atom loca-tions) (see Figure 2) with a point located on each of two contiguous bodies.In Figure 2, point p and point q constitute a hinge. Clearly, a typical bodymay contain one or more hinge points, but a hinge may be associated withonly two bodies. Motion across hinges represents relative motion betweenthe two adjacent bodies.

Hinge 1 (Figure 2) is given special consideration. It is also a pair of points;but one of the pair is coincident with the reference point of body 1, and the

Figure 1

Body reference point

Hinge

Sensor point

1

2

3

4

51

2

3

4 1

2

3

4

5

6

Internalframe

z

y

x

0


MBO(N)D 19

other point of the pair is coincident with the inertial origin. Motion acrossthe hinges is used to represent system motion. The reference point of body1 is located with respect to the inertial origin by an inertially referencedposition vector. The attitude of the reference frame of body 1, with respectto the inertial frame, is represented by three Euler angles. Thus, six posi-tion/attitude coordinates are associated with hinge 1.

Each of the remaining hinges is considered in a manner somewhat similarto that of hinge 1. Referring to Figure 2, note that there is an orthogonal ref-erence frame attached to point p and another to point q. Now six relativeposition/attitude coordinates are associated with the hinge of points p andq. Point q is located from point p with a p-frame referenced position vector.The attitude of the q-frame with respect to the p frame is represented bythree Euler rotations. Thus, if NH is the number of system hinges, 6 × NHposition coordinates are used in conjunction with modal displacementcoordinates for defining the system’s position state. Only the time-variableposition coordinates of the 6 × NH set of candidates are considered state-vector elements. (The position coordinates whose rates are constrained tozero are not included; however, the position coordinates themselves neednot be zero.)

Interaction forces can be applied to each of the atoms in each body. Theiroverall effect on the body’s dynamics is determined by summing up the ato-

Figure 2

p

n

m

q

l

force

torque

20 MBO(N)D


mistic forces to obtain the body force vector, summing up the moments(about the body reference) to obtain the body torque vector, and multiply-ing by mode shape vectors to obtain the body’s modal force vector. In addi-tion, atom coordinates and velocities can be calculated from the multibodyvariables (displacement vectors, Euler angles, modal amplitudes, and theirtime derivatives).

Substructuring the macromolecular model

Because of the order-N-multibody dynamics algorithm (Chun et al. 1987)based on the developments described above, MBO(N)D constitutes a newapproach to modeling macromolecular systems. As mentioned (Introduc-tion), the method is based on the idea that the essential dynamics of suchsystems is captured by the low-frequency modes of the model (Levy et al.1984; Ichiye & Karplus 1991; Horiuchi & Go 1991; Space et al. 1993;Amadei et al. 1993; Mizuguchi et al. 1994).

The MBO(N)D approach is based on substructuring a large molecularmodel into bodies and particles. You should base the substructuring on theamount of motion expected between atoms. For regions where motions areexpected to be very small, you group the atoms into rigid bodies. Regionsin which large conformational changes are expected should remain atomis-tic or be substructured into small bodies.

Generating component modes for flexible bodies

The purpose of component mode generation is to obtain a set of modeshapes for the bodies of the system, with the goal of capturing the essentialcharacteristics of the system while using as few modes as possible. Arelated area that has seen much interest in recent years is the efficient cal-culation of system modes (normal mode frequencies and mode shapes ofthe entire system) from component modes. The techniques used for gener-ating system modes from component modes and for generating componentmodes from system modes are similar.


MBO(N)D 21

System modes versus component modes

While the concept of component modes has been familiar to structuralengineers and dynamicists, it has seldom been used in molecular dynamicsmodeling. The term component modes refers to a set of modes used todescribe a portion of the modeled system. For molecular dynamics applica-tions, you can think of them as forming a basis set for the group of atomsthat comprise the “component” or body. The term itself does not imply anyparticular method for obtaining this basis set. The term system modes isused to refer to basis sets for the entire system. It also does not imply theuse of any particular solution method. For example, system modes can beobtained by normal mode analysis or covariance mode analysis.

Historically, the component mode technique was developed to overcomecomputational limitations in the solution of finite element problems. Anairframe, for example, may be modeled by tens of thousands of finite ele-ments. At the time, it was impossible to directly solve the eigenproblem forsuch a large system. The component mode approach divides the probleminto two stages. The first stage solves for the eigensolution for each com-ponent, such as the fuselage, the wings, the tail, modeled as independentpieces. Since the individual components involve fewer finite elements, theeigensolution for the components is a much more tractable problem. Oncethese component modes are calculated, a reduced set of low-frequencymodes are retained. In the second stage, the reduced set of componentmodes is used, together with boundary conditions between components, toassemble a mode-based reduced-order representation of the entire struc-ture. Since this reduced representation has fewer degrees of freedom thanthe original system, the eigensolution for the system modes now becomesfeasible.

Many component mode generation techniques have been developed (Ben-field & Hruda 1971; Craig 1977; Lee & Tsuha 1994)). These differ in theboundary conditions used, as well as in the augmentation by static modes(i.e., modes based on static deformations). In MBO(N)D, two types of com-ponent modes (vacuum modes and fixed environment modes) reflect theuse of different boundary conditions for the molecular component. The useof component modes for generating system modes has recently beenadapted by several researchers to the problem of solving for the normalmodes of large macromolecules (Hao & Harvey 1992; Hao & Scheraga1994; see also Durand et al 1994).

22 MBO(N)D


In addition to being used as an intermediate step in the solution for systemeigenvectors, component modes have been used for multibody dynamics todescribe the deformational motions of flexible components that areattached to each other by various types of joints. Motions between adjacentbodies may be arbitrarily large. Examples of such multibody systemsinclude space-based robots with relatively flexible arms (the remote manip-ulator system on the space shuttle) and flexible radiometers that spinaround an axis, involving large angular motions between spacecraft bus andradiometer.

For multibody dynamics applications, component modes describe defor-mational motions that are relative to a reference frame fixed in the body.This body reference frame follows the motion of the body and therefore canhave arbitrarily large motions relative to the inertial frame. Thus, in addi-tion to the component mode degrees of freedom, each body also has sixrigid degrees of freedom, modeled by three translation vectors and a set ofthree Euler angles or four Euler parameters. The use of these angular coor-dinates, instead of rotational mode shapes, allows large motions to be mod-eled.

Mode generation involves several issues: the interactions to be included inmode generation, the coordinates from which to start the generation pro-cess, and the selection of modes to retain. Two sets of mode generationboundary conditions are available in MBO(N)D.

The first set of boundary conditions uses the Hessian matrix for the body,in the absence of the rest of the system. We refer to the resulting set ofmodes as vacuum modes, since it is equivalent to the modes of the body ina vacuum. This set of modes is simple to calculate, since it does not requireknowledge of other parts of the model.

The second set of mode generation boundary conditions uses a Hessianmatrix that is calculated assuming that the rest of the system is fixed in iner-tial space. We refer to this set of modes as fixed environment modes. Theadvantage of this approach is that it accounts for some of the effects ofinteraction with the rest of the system. A disadvantage is that the fixed envi-ronment may be overly restrictive on the low-frequency motions of thebody.

For either of the two mode-generation methods, the procedure is quitestraightforward. The Hessian matrix for the entire system can be dividedinto partitions that represent the bodies of the system:


MBO(N)D 23

Eq. 3

To calculate the fixed environment modes for body A, for example, we sim-ply diagonalize the partition HAA after mass weighting it. To obtain the vac-uum modes for body A, we modify the assembly process to exclude thecomponents that arise from interactions between atoms in body A andatoms outside of it. Diagonalization of the resulting mass-weighted Hessianpartition then yields the vacuum modes.

The Hessian matrix that we use in MBO(N)D is based on a harmonic poten-tial approach similar to that developed by Tirion (1996) and Bahar andcoworkers (1997).

The instantaneous geometry of the body is assumed to be an equilibriumstructure. Instead of using the full CHARMM potential for calculating theHessian, we use a simplified potential which is either a single parameterharmonic potential (as in Tirion or Bahar), or a somewhat more realisticpotential that we have developed.

In our approach, interactions are accounted for solely by means of linearspring relationships between atoms. The force constants for these springsare derived from the CHARMM forcefield and only bond, angle and vander Waals effects are included. Electrostatic interactions are ignored and ashort cutoff is applied to the van der Waals interactions.

Another attractive property of this approach is that the eigenvectors are lesssensitive to small changes in coordinates. A full description of availablechoices is given in Appendix D, Commands—Standalone Mode. In standa-lone mode you can also choose to use the regular Hessian from CHARMMinstead of the harmonic approach described above.

HAB

HBB

HCB

24 MBO(N)D


Temperature

Precautions

As with all matters regarding temperature in dynamics simulations, youmust carefully monitor what is happening with the parameters you select.Be aware that there are fewer degrees of freedom in a multibody dynamicsrun, and so forced temperature changes may produce quite different resultsthan a corresponding atomistic run. Since temperature changes areachieved by a uniform rescaling of velocities, be careful that this doesn’texaggerate temperature differences across different regions of the system.

For example, if the system has small bodies, large temperature changesmay require more time to equilibrate through the entire system than in anatomistic run. Select your control parameters carefully and examine yourresults to ensure that they are working as expected.

How temperature is controlled

Support for temperature control in MBO(N)D dynamics varies for differentMD modes: heating, equilibration, and constant-temperature runs. HEAT-ING and EQUILIBRATION are implemented in the same manner as instandard atomistic runs in CHARMm (i.e., with the same controls for fre-quency, temperature ranges, etc.). The one difference is that only velocityrescaling is supported after the initial assignments. In other words, all ofCHARMm’s current mechanisms may be used to assign an initial temper-ature but it can be changed thereafter only by scaling velocities. In particu-lar, assigning a range of velocities is possible only at the beginning of a run.

CONSTANT TEMPERATURE runs are implemented using a simpleBERENDSEN thermostat. Again, the control keywords for this are identi-cal to those for CHARMm atomistic runs, i.e., you can specify the desiredtemperature and a coupling rate, which determines how quickly the exist-ing temperature is changed to the target temperature.

You can monitor the temperature of bodies and of atomistic regions sepa-rately. If you select a print level of 2 or greater (MBPLevel in theDYNAMIfcCS command), these temperatures are periodically printed tothe output file. The frequency is controlled by TFREQ.

Constraints during dynamics simulations

MBO(N)D 25

One point to note is that the use of exact constraints (HINGE BOND), andthe general reduction of degrees of freedom in MBO(N)D, affects the tem-perature assignment. The reduction in the number of available degrees offreedom is split between each end of each constraint (e.g., between twobodies or between a body and an atomistic region). The reduction of thedegrees of freedom but not the forces results in increased sensitivity to localtemperature changes. As a result, you should be careful to equilibrate thor-oughly before running MBO)N)D and to change temperature slowly.

Constraints during dynamics simulations

Constraints for bond lengths and bond angles are important elements inmolecular dynamics simulations. They are typically used in an attempt toeliminate the small time constants that are attributable to bond-stretchingand angle-bending terms. In MBO(N)D, constraints are handled by anorder-n recursion algorithm.

In MBO(N)D, the relevant constraints are bond-length constraints and areapplied across covalent bonds that exist between bodies and particles. Formodels involving flexible bodies, the mode shapes (whether vacuummodes or fixed environment modes) do not account for fixed bond lengthswithin the bodies. Thus, the specification of bond length constraints affectsonly those covalent bonds that are outside bodies.

Constrained multibodyequations of motion in gen-eralized coordinates

The dynamics equation for a system of particles or bodies can be written inthe following general form:

Eq. 4

The vector U is a system level variable that contains the three componentsof absolute velocity for each particle, as well as absolute translational androtational velocities in body frame coordinates for rigid bodies. If any ofthe bodies is flexible, the vector U also includes the modal velocities forthose bodies. M is a block diagonal matrix of inertia matrices, G is a vectorof generalized forces, B is a matrix of kinematic coefficients, is a con-straint selection matrix, and Λ is a vector of generalized constraint forces,or Lagrange multipliers.

The hinge kinematics of the system can be written as:

Eq. 5

MU·

G BTΦΛ+=

Φ

β· BU=

26 MBO(N)D


where is a vector of relative velocities between particles and bodies.

Selection matrices and are used to extract the free and constrained rel-ative degrees of freedom, respectively:

Eq. 6

For free degrees of freedom:

Eq. 7

For constrained degrees of freedom:

Eq. 8

The variable is zero for fixed degrees of freedom, which is the most com-mon type of constraint.

Integration algorithms

Numerical integration of the MBO(N)D equations of motion is performedby a Lobatto algorithm. The Verlet-type integrators that are commonly usedfor molecular dynamics are not directly applicable to the MBO(N)D equa-tions because of the dependence of the accelerations upon the velocity vari-ables. These velocity-dependent terms arise from gyroscopic and Corioliseffects, as well as from kinematic constraints and deformation-dependentinertia elements.

Lobatto integrator The Lobatto algorithm is actually very similar to the velocity Verlet algo-rithm. The velocity variables are propagated to the half step, and the posi-tion variables are propagated to the full step:

Eq. 9

where v(t) is the velocity state, x(t) is the position state, the a term is accel-eration, and ∆t is the integration step. Since the velocity at the half step is

β·

Φ Φ

β· Φβ·f

Φα·+=

β·f

ΦTβ· ΦTBU= =

α· ΦTβ· Φ

TBU= =

α·

v t∆t2-----+

� �� v t( ) a x t( ) v t

∆t2-----+

� �� , ∆t

2-----+=

x t ∆t+( ) x t( ) v t∆t2-----+

� �� ∆t+=

Brief description of the MBOND/CHARMm interface

MBO(N)D 27

present in both the left- and right-hand parts of the equation, it needs to beiterated using, for example, the initial guess based on the prediction:

Eq. 10

The full-step velocities are then obtained using the following equation:

Eq. 11

The number of forcefield evaluations (which are dependent only upon posi-tions) is the same as for Verlet integrators.

MTS Lobatto integrator A time-reversible multiple-time-scale (MTS) variant of the Lobatto inte-grator has been implemented in MBO(N)D. It allows nonbond interactionsto be evaluated at different rates, depending on a mass-based criterion forseparation of time scales. You can specify as many as five time scales orallow MBO(N)D to determine them automatically.

Brief description of the MBOND/CHARMm interface

Even though MBOND is a module within the Insight II molecular model-ing program, the calculations are actually run by a new molecular dynamicsprogram that combines an MBO(N)D dynamics engine with the CHARMmmolecular mechanics code. This new code is called MBOND/CHARMm.

The MBOND/CHARMm interface has two main elements:

© Three calls from CHARMm to MBO(N)D, which pass the setup infor-mation generated within CHARMm to MBO(N)D and invoke dynam-ics.

© Two callbacks from MBO(N)D to CHARMm—The first computesforces, and the second mimics the control logic of DCNTRL to providerescaling, printouts, and file saving at appropriate intervals.

The first part of the interface (CHARMm to MBO(N)D) is divided intothree separate interface routines. This division highlights the logical stepsof setting up the system and allows more flexibility within CHARMm(both on the user level and on the level of the code).

v0 t∆t2-----+

� �� v t( ) a x t( ) v t( ),[ ] ∆t

2-----+=

v t ∆t+( ) v t∆t2-----+

� �� a x t ∆t+( ) v t

∆t2-----+

� �� , ∆t

2-----+=

28 MBO(N)D


The three interface routines are:

© MBTOPOL—Passes the topological information, i.e., the body sub-structuring and connectivity. Invoked by the keywords MBONd/SUB-Structure.

© MBMODPUT—Passes the mode information (mode shapes) for all theflexible bodies. Invoked by the keywords MBONd/MODEs.

© MBDYNA—Passes the atomic properties (coordinates, velocities,forces, mass, charge) and the run-time control parameters (frequencies,restart etc.) and activates MBO(N)D’s dynamics. The properties arepassed only at this point because in CHARMm the velocities areassigned only by the DYNAmics command. Invoked by the keywordsMBONd/DYNAmics.

The advantage of this scheme is that it allows for:

© Manipulating the system (e.g., the coordinates) between setting up theMBO(N)D interface and actually invoking the DYNAmics MBONdcommand.

© Updating the mode information during the job (on the fly) without hav-ing to pass the topological interface again (e.g., changing a body fromFLEX to RIGID during a single run).

Once MBO(N)D dynamics has started, MBO(N)D controls the run untilcompletion. However, it relies on CHARMm for force computation andsome control logic. This second part of the interface (MBO(N)D toCHARMm) consists of two routines:

© MBFORCE—Computes CHARMm forces for MBO(N)D, given a setof atomistic coordinates.

© MBCTRL—Takes care of printing output, file saving, and temperaturescaling.

MBO(N)D 29

3 General Methodology

Why read this section To exploit the full potential of MBO(N)D’s substructured moleculardynamics methodology, you need to choose an appropriate strategy for themodel being studied. This section presents substructuring strategies andadditional aids to successful substructured modeling and simulation of pro-teins using MBO(N)D.

Substructured molecular dynamics, as enabled by MBO(N)D, presentsnumerous possibilities for substructuring a molecule or molecular system.A substructured model may contain particle (atomistic) bodies, rigid bod-ies, and flexible bodies (with varying numbers of modes), in any combina-tion you see fit. This results in very many possible combinations. Thechoice of a proper substructuring for a given problem can depend on themodel, its motion, its function, its environment, and the particular aspect ofthe molecule’s dynamics that you want to investigate, i.e., the essentialdynamics. The task of finding a near-optimal substructuring to attain max-imum computational performance, while ensuring accurate results giventhe essential dynamics of interest, is an open problem.

The following sections include a sampling of possible substructuring strat-egies as well as lessons learned from research in substructuring. The pre-sentation highlights the underlying philosophy and fundamental tradeoff atthe heart of MBO(N)D: substructured molecular dynamics enables muchfaster/longer molecular dynamics runs at the expense of uninterestingdetailed motion, while capturing the essential dynamics of interest.

Substructuring strategies

Molecular domains

As mentioned above, MBO(N)D performance results from ignoring unin-teresting, high-frequency details in favor of lower-frequency, essentialdynamics. Large global motions, such as those that occur between large

30 MBO(N)D

3. General Methodology

molecular domains, are a good example of the type of essential dynamicsMBO(N)D can reproduce well while attaining a large computationalspeedup.

To substructure such a model, you first should identify the two or moredomains and the linker regions between domains. The linker regions needto be more finely substructured than the domain regions. In addition, due tothe typically correlated nature of the sidechain motions of sidechains nearthe inter-domain/linker region, these need to be substructured more finelyas well (see Sidechain substructuring). The portions of the domains awayfrom the linker region can be substructured into much larger bodies. Thedisparity in body sizes and the associated disparity in time scales for thedynamic simulation can be handled best with the MTS integrator (see MTSintegrator).

Alpha helices and pseudodihedral angle analysis

How to identify regions oflow motion

It is natural to expect that structurally well defined alpha helices and betasheets, whose atoms exhibit concerted motions, would be good candidatesfor grouping into rigid or flexible bodies. However, indescriminatelygrouping the constituent residues of such secondary structures (as definedin the Brookhaven PDB, for example) into bodies does not necessarilyyield good results. The reason is that statically defined secondary structuresmay actually exhibit considerable motion at the ends of the helical regionsthat is not well correlated with motions of the interior residues of that heli-cal section.

We need a way of identifying “dynamic” secondary structures, i.e., the coreresidues of the static secondary structure that maintain their stiffnessthrough the hydrogen-bonding structure during molecular dynamics. These(generally shorter) dynamic secondary structures are excellent candidatesfor substructuring into rigid or flexible bodies. The choice between rigidand flexible depends on both the amount of internal motion expected andthe importance of that motion to the dynamic property being studied.

A good way to identify these dynamic secondary structures is to carry outpseudodihedral angle analysis with a preliminary short atomistic simula-tion.

Pseudodihedral angles are formed from the alpha carbon atoms of everyfour consecutive amino acid residues. The analysis consists of:


MBO(N)D 31

© Calculating the difference between the largest and smallest values ofeach pseudodihedral angle during the atomistic simulation.

© Plotting the maximum difference in pseudodihedral angle vs. pseudodi-hedral number.

© From this plot, developing a criterion to differentiate the model intobody and atomistic regions.

Best for alpha helices Pseudodihedral angle analysis can actually be used to identify any region(not just secondary structures) having small enough relative motions that itscomponent residues can be aggregated into bodies. However, it works bestfor identifying alpha helical regions whose residues can be grouped intobodies. A maximum pseudodihedral angle difference threshold of about45° generally works well for differentiating contiguous low-relative-motion residues from highly mobile regions (e.g., loops).

Beta sheets and interpeptide plane angle analysis

Beta sheets require a dif-ferent approach

Pseudodihedral angle analysis of beta strands (along the backbone) usuallyindicates that beta sheets have too much motion to be grouped into bodies.However, analyzing the motion of the beta sheet along its “ridges” (i.e., inthe direction of the hydrogen bonds, perpendicular to the backbone)enables the identification of nonconsecutive residues that exhibit low rela-tive motions and can therefore be grouped into rigid or flexible bodies.

A simplified analysis of the angle between nearby peptide planes (similarin spirit to the pseudodihedral angle analysis described under Alpha helicesand pseudodihedral angle analysis) has proved useful in identifying non-consecutive hydrogen-bonded residues (i.e., beta bridges). This analysisinvolves defining a vector between the consecutive C and N atoms alongthe backbone and considering these vectors pairwise for time points alonga trajectory. Those pairs with average midpoint distances greater than aspecified cutoff (say 8 Å) are discarded. For the remainig pairs, the rangeover the trajectory of the angle between the C–N vectors is recorded. Pairswith a maximum range below a specified cutoff are considered to be hydro-gen bonded and therefore good candidates for aggregation into the samebody.

32 MBO(N)D


Loops and turns

By their nature, loop and turn regions exhibit highly anharmonic motionsdue mostly to relative dihedral motions between residues. When necessary,you can model these regions atomistically. However, this limits the size ofthe smallest time step that can be used in the molecular dynamics simula-tion. You should therefore substructure loop and turn regions into the larg-est possible bodies that allow the essential function of these regions to beexpressed.

Several loop-substructuring strategies are useful in achieving this balance:

© Divide the loop region into few rigid or flexible bodies, making use ofa higher threshold in pseudodihedral angle analysis.

© Group two–three consecutive residues into bodies, being careful toinclude entire peptide planes in a body (that is, do not split the peptideplane atoms into separate bodies).

© Consider the peptide planes (amides) as rigid bodies and the sidechains(starting at the beta carbon) as rigid or flexible bodies. Treat the alphacarbon and hydrogen atoms atomistically.

© Same as above, but include the Cα and its hydrogen atom as part of thesidechain body.

Sidechain substructuring

Sidechains can be substructured independently of the backbone, as multiplerigid or flexible bodies, or they can be treated atomistically. A sidechain χ-angle analysis over a short atomistic run (similar in approach to the back-bone pseudodihedral angle analysis) is effective in helping to decide on asubstructuring scheme for sidechains.

Important

In general, amino acid sidechains should become part of the larger bodydefined by pseudodihedral angle analysis of their alpha carbons. However,it is possible that a long flexible sidechain such as arginine may exhibit sig-nificant motion independent of the low relative motion of the backbone (for

Maximal aggregation into bodies is needed to fully exploitMBO(N)D’s ability to use long time steps. This usually means thatmost sidechains should be subsumed into larger multi-residue bodies.


MBO(N)D 33

example, in a portal region or near an active site). If you consider thismotion essential for the dynamic property being studied, then suchsidechains should be substructured independently of the backbone.

A good way to judge overall sidechain motion for a given residue is to lookat the range of motion of the angle formed by the vector from N to C of theresidue and the vector from Cα to an atom at the sidechain terminus.

Lessons learned

This section summarizes some top-level substructuring strategies that,through the course of our research into substructuring, we have found tohelp in attaining maximum performance when running MBO(N)D.

The largest speedups that can be achieved with MBO(N)D arise through theuse of very large timesteps. To attain these large timesteps without precip-itating numerical instability in the dynamic integration algorithm, it is nec-essary to reduce the instantaneous high frequency content of the dynamictrajectory. In MBO(N)D this is done mainly through substructuring intolarge bodies. The larger mass of these bodies helps decrease the frequencyof the motion. The logical conclusion is that the largest possible bodiesshould be used. The tradeoff, however, is reduced accuracy of the dynamicsimulation if bodies are used that are too large to describe the interestingessential dynamics.

Similar to the molecular domain substructuring described under Substruc-turing strategies, a range of body sizes is likely required for the accuratereproduction of the essential dynamics of a problem. We refer to this capa-bility of MBO(N)D as multigranularity. When taking advantage ofMBO(N)D’s multigranularity, you should consider using the multiple timescale (MTS) integrator (see MTS integrator).

The best balance between computational performance and essentialdynamics accuracy to date has been achieved by using consecutive 2–3-res-idue rigid bodies for the entire protein. Studies on hinge-bending and glob-ular proteins suggest, however, that both sidechain substructuring andlarger bodies with component modes play an essential role for certainclasses of problems.

34 MBO(N)D


Other analytical methods to aid substructuring

Preparing and carrying out a pseudodihedral analysis can be time-consum-ing. In addition, interpretation of the pseudodihedral results can be compli-cated by differences between different atomistic runs. Thus, alternativemethods that provide either a reasonable quick guess or confirmation of theresults of the atomistic dynamics are helpful. Three methods are discussedhere.

Analysis of B-factor data

During structure refinement from crystal or NMR data, isotropic thermalfactors are frequently calculated, and many X-ray and NMR structures inthe Brookhaven PDB include temperature factors (or B factors). These fac-tors are proportional to the mean square displacement of that atom and rep-resent thermal motion about the equilibrium structure. The higher thethermal motion, the less likely that this structure should be substructured asa semirigid or rigid MBO(N)D body.

To analyze the B factors, you need to plot the average B-factor values forthe backbone atoms of each residue of your protein vs. the residue number.

Peaks in B-factor values that correlate with peaks found from similarpseudodihedral plots derived from an atomistic simulation of the proteinhelp confirm the pseudodihedral analysis of flexibility.

A B-factor analysis alone might also be used as a simplified first-guessbasis for substructuring the protein.

Note

Difference between two experimental conformations

Two or more different experimental conformations have been determinedfor many biological structures, for example, the open and closed forms ofHIV protease and the R and T forms of hemoglobin. By determining thedifferences between such conformations, you can create a map of the pointsabout which movement must have occurred, which thus might be consid-ered flexible joints in the dynamic structure.

B-factors do not yield information on correlated motions and for thisreason do not reveal details of the relative motion between and withincandidate bodies. Thus, B-factor analysis can provide only a roughfirst guess for substructuring.


MBO(N)D 35

The results might help confirm the results of a pseudodihedral analysis orbe used as a first-guess basis for substructuring the protein.

Secondary structure calculation

Since secondary structural components like alpha helices and beta sheets(as well as disulfide bonds) constitute semirigid hydrogen-bonded (andcovalently bonded) networks, it is logical to group regions based on theircalculated secondary structures.

Calculate contiguous secondary components using a method such as that ofKabsch and Sander (available in the Homology module of the Insight IIprogram). Visualizing the changes in secondary structure definition over ashort atomistic trajectory helps you to identify the dynamic secondarystructures (i.e., those that retain their integrity during dynamics). Commer-cially available packages exist to carry out this visualization (e.g., DSSP).Then define each identified contiguous secondary component as a body(either rigid or flexible) and divide each adjoining nonsecondary group ofresidues into smaller peptide plane and sidechain bodies or into small 2–3-residue bodies with hinges at the φ or ψ angles.

Hydrogen-bonded beta sheets may be grouped into one large body (but seeClosed loops increase computation expense), each alpha helix may begrouped into one body, and the remaining residues may be grouped intosmaller 2–3-residue bodies with sidechain bodies as needed. Other hydro-gen-bonded networks, such as those involving sidechains, may also bedefined as semirigid bodies.

Substructured dynamics and topological loops

Distance constraints canlead to closed topologicalloops

Whenever distance constraints are specified for an MBO(N)D substruc-tured simulation, closed topological loops might occur (because MBO(N)Denforces constraints exactly, by removing the corresponding degrees offreedom). Examples of closed loops include aromatic sidechains (if mod-eled atomistically), disulfide bonds (if the loop is not completely enclosedwithin one body), and cross-strand beta-sheet bodies (sometimes).

Closed loops increasecomputation expense

MBO(N)D has no problem handling closed topological loops; however, asthe number of closed loops increases, so do the required computationaltime and memory.

Therefore, you should try to limit the number of closed topological loopsin your substructured model to no more than two or three.

36 MBO(N)D


Alternatively, you can decide not to use distance constraints (for example,by selecting the HINGE OFF option for the MBOND SUBTructure key-word in standalone mode or by not selecting the Bond_Constraints param-eter in the SetUp/Dynamics pulldown), allowing the forcefield to maintainthe appropriate distances between atoms that are covalently bonded acrossadjacent bodies.

Choice of reference coordinates and selection of modes

The proper choice of reference coordinates for component mode generationis very important for obtaining good simulation results. The use of a har-monic potential for calculating MBO(N)D component modes is veryadvantageous because the resulting modes are insensitive to small changesin position, and mode selection is as easy as just selecting the first fewmodes. The ability to do this is partly due to the fact that the reference coor-dinates for harmonic potential modes are treated as equilibrium coordinatesfor calculating the system Hessian matrix. In contrast, normal modes areusually computed for the model using its minimum-energy state as the ref-erence coordinates for calculating the system Hessian matrix. The resultingmodes are thus valid in a region around this minimum-energy state. Themolecule at room temperature may have an instantaneous structure that isfar away in conformation space from the minimized structure. Conse-quently, the modal model computed about the minimum coordinates wouldnot adequately describe the structure. Thus, to obtain a set of componentmode shapes that represent the model well at room temperature (or othercondition), it is better to use a set of reference coordinates that is conforma-tionally close to the structures that predominate under the modeled condi-tions.

The goal of mode selection is to define the low frequency subspace inwhich the atoms of the body are allowed to move. In this manner we cap-ture the more important low frequency motions and ignore the unimportanthigh frequency motions. Selection of only the low frequency modes alsoallows the integration time step to be large, requiring fewer integrationsteps for completion.

Initial coordinates and velocities

MBO(N)D 37

Initial coordinates and velocities

The initial conditions for MBO(N)D position and velocity variables areobtained by least-squares fitting with the atomistic coordinates and veloci-ties. Thus, MBO(N)D can be started from the same set of input files (.psf,.crd, or .rst) that an atomistic CHARMm run starts from (thus the outputfiles (.rst, .crd files) of an MBO(N)D run can also be read in by CHARMmto start an atomistic simulation). The least-squares fitting procedure is usedonly during initialization.

For the positional variables, the least-squares fit is performed to solve forthe displacement vectors from the inertial frame origin to the body frameorigin, the rotational transformation matrices that orient the body frameswith respect to the inertial frame, and the modal amplitudes of each body.Bond length constraints are also imposed for covalent bonds between bod-ies, if it was specified for the simulation.

For the velocity least-squares fitting, the velocity vectors, angular velocityvectors, and modal velocities are solved for in a one-time calculation. Thisis because the fitting problem is linear and therefore requires no iteration.The fitting also includes derivatives of the bond-length constraints, if thesewere used for the position fitting. Furthermore, six additional constraintsare applied to the velocities, such that the MBO(N)D model’s linear andangular momenta match those of the input atomistic conditions. (These canbe set to zero by using ISCALE 1 and SCALE 1.0 in the DYNAMICScommand.)

After the positional and velocity variables are computed, they are easilyconverted into relative coordinates and relative velocities to initialize theMBO(N)D dynamics integration.

Stages and duration of dynamics simulation

Atomistic or MBO(N)D runs can be used to heat and equilibrate the systembefore starting MBO(N)D data-collection runs. The following exampleassumes you are using atomistic runs to heat and equilibrate. Further equil-ibration is required when you begin a substructured molecular dynamicsrun.

An example procedure is:

38 MBO(N)D


1. Obtain a starting configuration (from the PDB, for example).

2. Add hydrogen atoms if necessary, using (for example) CHARMm’sHBUILD facility.

3. Minimize the model to relieve bad contacts. A sample input is givenbelow:

* CHARMm title here* Example minimization script*

!USER TO ENTER SEGID NAME HERESET S 1ctf !(SEGID_NAME)

COOR COPY COMP !PUT INIT COOR IN COMP ARRAY

!---SETUP SOME DEFINITIONS. ADD MORE IF NEEDED ---DEFINE BACK SELE SEGID @S .AND. (TYPE N .OR. TYPE CA .OR. TYPE C -

.OR. TYPE O) ENDDEFINE SIDE SELE ALL .AND. .NOT. BACK END!-----------------

!a) minimize artificially added hydrogen

CONS FIX SELE NONE ENDCONS FIX SELE .NOT. TYPE H* ENDMINI ABNR NSTEP 200 NPRINT 50

!b) minimize the side-chains. (Fixing the backbone atoms)

CONS FIX SELE NONE ENDCONS FIX SELE back ENDMINI ABNR NSTEP 500 NPRINT 50

!c) Then minimize with Ca atoms fixed.

CONS FIX SELE NONE ENDCONS FIX SELE TYPE CA ENDMINI ABNR NSTEP 500 NPRINT 50

!d) Finally do minimization with using all atoms

CONS FIX SELE NONE ENDMINI ABNR NSTEP 500 NPRINT 50

!NOW SEE HOW MUCH THINGS HAVE CHANGED FROM INIT COOR!USER CAN ADD MORE HERECOOR RMSCOOR RMS SELE BACK ENDCOOR RMS SELE SIDE END

GETE !for testing

stop

Dynamics output

MBO(N)D 39

4. Bring the model from an initial temperature of 50 K to the desired tem-perature.

5. Equilibrate the model at the desired temperature until thermodynamicparameters have stabilized.

6. Perform the atomistic data-collection dynamics run, which can be ofany length.

7. Perform pseudodihedral or other analysis on the results of the atomisticdata-collection run. (The results are used for substructuring the model.)

8. To determine the modes for flexible bodies, take the configuration thatwill be used for initializing the MBO(N)D simulation (usually a pointalong the atomistic equilibration trajectory) and minimize that modelfor several cycles to remove any bad contacts.

9. Determine the modes from the minimized coordinates from Step 8.

10.Start an MBO(N)D equilibration using the coordinates from the desiredpoint from the atomistic equilibration trajectory (usually the finalpoint).

11. Finally, perform the MBO(N)D data-collection run.

Dynamics output

The output of an MBO(N)D dynamics simulation includes the same infor-mation as is generated during an atomistic CHARMm simulation, togetherwith additional information pertinent to the body-based approach.

The standard CHARMm dynamics files (trajectory, velocity, energy, andrestart files) are supported during multibody dynamics. Energy files havean additional line of BODY specific information per entry. Trajectories canbe analyzed as usual and runs can be restarted in CHARMm as needed.

The energy reporting, controlled by NPRINT (in CHARMm), has an addi-tional line of information at each step, which specifies the following terms:

© Deformation energy.

© A null value (0 0) reserved for future use.

© Momentum.

© Temperature in the body regions.

40 MBO(N)D


© Temperature in the atomistic regions.

MBO(N)D 41

4 Methodology—Insight

This section is a general description of how to use the MBOND module ofthe Insight program. The on-line help utility contains further details aboutwhat individual commands and parameters do. On-line help (accessed byclicking the help icon) also presents information about parameters andcommands.

Commands provided in the MBOND module are discussed in general termsin the order in which they are used in typical simulations. Also included arehints about when certain parameter values should or should not be used.

If you are unfamiliar with such concepts as bodies and modes, pleasereview Chapter 2, Theory and Implementation. Substructuring strategiesand procedures are discussed in greater detail in Chapter 3, General Meth-odology.

Using MBO(N)D in theInsight environment

The MBOND module is used to set up and then start an MBO(N)D calcu-lation. Unlike many commands in the Insight package, nothing actuallyhappens until the MBO(N)D job is started, making it possible to set upcomplex calculations and even (by temporarily leaving the Insight environ-ment to use a text editor) edit or change parts of the calculation before thejob is started.

Preliminary tasks

Before using the MBOND module, you should create separate workingdirectories for different projects and move to the appropriate directorybefore starting up Insight. Then start the Insight program, build or read ina model, and access the MBOND module.

Additional information Installing and starting the Insight program, some basic UNIX commands,use of the mouse and interface controls within Insight, terminology used inreferring to use of the Insight controls, model building, etc., are coveredseparately, in the documentation for the Insight program.

42 MBO(N)D

4. Methodology—Insight

Forcefields— including what they are, how to prepare the forcefield andthe model, how to impose constraints and specify how nonbond interac-tions are handled, and concepts and methods relevant to minimization anddynamics—are covered separately, in Forcefield-Based Simulations.

Specific CHARMm documentation is also supplied separately with theCHARMm program.

Accessing the MBONDmodule

To access the MBO(N)D commands, select MBOND from the Modulepulldown (that is, click the MSI logo, then choose MBOND from the listthat appears). The set of MBOND pulldowns then appears on the lowermenu bar.

Specifying the CHARMmforcefield

Select the Forcefield/Select command. Select the MSI CHARMm force-field, charmm.cfrc, and select Execute. The forcefield status window in thelower left-hand corner of the Insight window should now show charmm.

The default forcefield for MBO(N)D calculations is the MSI CHARMmforcefield (Momany and Rone, 1992), whose filename is charmm.cfrc.Alternatively, you may do calculations with the Harvard forcefields bychoosing charmm19.cfrc or charmm22.cfrc from the $BIOSYM/gifts/mbond directory.

NOTE: Refer to the README file in this directory for additional notes.The environmental variable MBOND_GIFTS must point to the directorywhich contains these files. For example, if these files are in the default loca-tion, type:

> setenv MBOND_GIFTS $BIOSYM/gifts/mbond

Whenever you change forcefields, nonbonded parameters are read fromparameter files. Subsequent simulations will also use these parameter filesunless you specify otherwise. Thus if you wish to use values other than thedefault for a forcefield, you must set these after choosing the forcefield.

After selecting the CHARMm forcefield you must use the Forcefield/Potentials command to Accept the potentials. This action applies the cor-rect CHARMm atom types to the model.

Preparing the model

MBO(N)D 43

Preparing the model

Minimizing the model

A preliminary atomistic minimization is almost always needed, to optimizethe model’s conformation before mode generation and the MBO(N)Ddynamics simulation is carried out.

Accessing the tools Select the SetUp/Minimize command from the lower menu bar.

Selecting run conditions Select the Minimization Method.

Set the other minimization parameters as desired (see the CHARMm doc-umentation and Forcefield-Based Simulations for additional informationon minimization).

Select Execute. The minimization parameters are now set up, but the jobdoes not run until you execute the MBOND_Run/Minimize command.

Substructuring

The first step in preparing your model is to substructure it, that is, to groupatoms into bodies. Use combinations of Molecule Spec, Property andSubstructure Method options (in the Bodies/Define menu) to define bod-ies.

The Molecule Spec param-eter box

The Molecule Spec parameter box enables the use of general Insight IIselection mechanisms. Use this function to select large portions of the mol-ecule, which you may later substructure further using the Property andSubstructure Method functions.

For example, to select residues 1-20 from molecule CTF for further sub-structuring, type CTF:1-20 in the Molecule Spec parameter box. To selecta specific residue type, enter CTF:TRP, for example.

Molecule Spec syntax is described in detail in the Insight II documentation.

The Property Name value-aid

The Property Name value-aid allows you to substructure a molecule usingKabsch_Sander, None, PDB_Classification, Pseudo_Dihedral,Sidechain_Vector and Temp_Factor options.

Use Kabsch_Sander or PDB_Classification to create bodies using Kab-sch-Sander or PDB classification of secondary structure elements. You

44 MBO(N)D


must read in a .pdb file containing descriptions of secondary structure ele-ments in order to use the PDB_Classification option.

Use the Pseudo_Dihedral option to analyze a trajectory or set of structuresto determine mobility of fragments of peptide chains. Pseudodihedral angleanalysis can actually be used to identify any region (not just secondarystructures) having small enough relative motions that its component resi-dues can be aggregated into bodies. However, it works best for identifyingalpha helical regions whose residues can be grouped into bodies.

Use the Sidechain_Vector option to analyze one or more loaded trajecto-ries to create sidechain bodies from residues for which sidechain mobilityis within a given value range. Sidechain mobility is measured as a range ofchange in an angle formed by two vectors, v1 and v2, where:

v1 is a vector between two atoms, N and C, with the residue, and

v2 is a vector between atom C-alpha and an atom at the end of thesidechain of the same residue.

When Sidechain_Vector is selected Chi_1 and Phi_Psi are the only validSubstructure Method choices.

Use the Temp_Factor option to generate a subset containing atoms with atemperature factor within a given value range. Note: any single-atom prop-erty (e.g., B-factors, H-exchange rates, etc.) which is an indicator of aver-age mobility of various atoms can be recorded in the fourth column of .crdor .pdb files and then used for substructuring via the Temp_Factor option.

The Substructure Methodvalue aid

The Substructure Method value-aid allows you to substructure a mole-cule using Beta_Bridge, Chi_1, Contiguous, None, Phi, Phi_Chi, Phi_Psi, Psi, and Psi_Chi options.

The Beta_Bridge option analysis involves defining a vector between twoconsecutive C and N atoms along the backbone, and considering these vec-tors pairwise for time points along a trajectory. Those pairs with averagemidpoint distances greater than a cutoff are discarded. For the remainingpairs, the range over the trajectory of the angle between the C-N vectors isrecorded. Pairs with a maximum range below a specified cutoff are consid-ered to be hydrogen bonded and therefore good candidates for aggregationinto the same body.

The Chi_1 method executes chi cuts on a subset determined by the speci-fied Molecule Spec and Property values. This results in bodies consistingof sidechains.

Preparing the model

MBO(N)D 45

The Contiguous method creates contiguous low-mobility bodies from sub-sets determined by the specified Molecule Spec and Property values.

For example:

Suppose our plot of fluctuation of pseudodihedral angle vs. pseudodihe-dral number (the results of selecting Property/Pseudo_Dihedral)shows three high (>45 degrees) value ranges surrounding two “valleys”with low (<45 degrees) value ranges. If we specify < 45 as the Contig-uous value range, two bodies consisting of consecutive residues withlow pseudodihedral mobility will be created.

The Phi method executes phi cuts on a subset determined by the specifiedMolecule Spec and Property values.

The Phi_Chi method cuts phi angles on the subset according to the Resi-due Cut Rate value and all chi angles in Molecule Spec.

The Phi_Psi method executes phi-psi cuts on the subset specified in Mol-ecule Spec and Property. This results in bodies consisting of sidechains +C-alpha atoms.

The Psi method executes psi cuts on the subset specified in Molecule Specand Property.

The Psi_Chi method cuts psi angles according to the Residue Cut Ratevalue and all chi angles in Molecule Spec.

Choosing substructuringoptions

Combinations of Molecule Spec, Property and Substructure Methodoptions make it possible to generate virtually any of the substructuringstrategies described in Chapter 3, General Methodology.

Intuitively the most obvious type of substructuring is one in which thewhole peptide chain is first subdivided into high and low mobility regions.Low mobility regions may be divided into relatively large bodies. Furtherdivide regions of high mobility into smaller bodies.

This type of substructuring can be accomplished using the PropertyName/Pseudo_Dihedral and Substructure Method/Psi (or Phi) options.

For example, load a precomputed atomistic trajectory using the DeCiphermodule. Select Property Name/Pseudo_Dihedral.

For low mobility regions use Value_Range <=45 and a Residue Cut Rateof 4. This results in the formation of large, four-residue bodies for theselected low mobility region.

46 MBO(N)D


For high mobility regions (loops) use Value_Range >=45 and a ResidueCut Rate of 2.

To more finely substructure loop regions, use Chi_1 or Phi_Psi instead ofPhi. Using Chi_1 results in sidechain bodies and one backbone body.Using Phi_Psi results in sidechain + C-alpha bodies and peptide plane bod-ies.

Secondary structure analysis (using Kabsch_Sander and PDB_Classifi-cation properties) combined with the Beta_Bridge substructuring methodcan be useful in forming beta-bridge bodies. You can group residue pairs(or triples) with low relative mobility into bodies by selecting the Kabsch_Sander option (set Value Range to SHEET) and applying Beta_Bridgeanalysis to the regions of the protein hydrogen bonded across peptidestrands.

Sidechain substructuring is mostly useful as a second-order method. It isapplied typically to larger bodies already existing in the system to deter-mine if mobility of the sidechains is high enough to justify putting theminto separate bodies. Sidechain analysis is often used in conjunction withthe Phi_Psi cut substructure method. All high mobility sidechains from thisregion are then put into sidechain + C-alpha bodies, and remaining peptideplanes form separate bodies.

Any single-atom property (e.g., B-factors, H-exchange rates, etc.) which isan indicator of average mobility of various atoms can be recorded in thefourth column of .crd or .pdb files and used for substructuring (using theTemp_Factor property). This data can be used to divide all atoms in thesystem into high and low mobility regions and select different kinds of cutsappropriate for those regions.

Three simple examples are given here. For more extensive samples consultPilot tutorial Lesson 2: Using Sidechain Vector Analysis from the Semiau-tomated Panel.

Example 1

Select Create.

Select Property Name/None.

Select Substructure Method/Phi.

Execute.

Preparing the model

MBO(N)D 47

Example 1 should produce bodies by grouping together three (the defaultvalue in Residue Cut Rate) consecutive residues into bodies and applyingphi cuts. Bodies will be automatically assigned consecutive names (BDY1,BDY2, etc.) and colors.

Example 2

Load a trajectory using DeCipher.

Select Bodies/Define from the menu bar.

Select Create.

Select Property Name/Pseudo_Dihedral.

Enter <30 in Value_Range.

Select Substructure Method/Contiguous.

Execute.

Assuming that there are alpha helices in the system this should produce rel-atively large bodies, with contiguous residues for which pseudodihedralangles (defined by four consecutive C-alpha carbons) have fluctuationssmaller than 30 degrees. Residues in loops between helices remain unsub-structured.

If we select Preview instead of Create and turn on Create_Graph we canproduce a graph similar to the one displayed below.

Higher mobility loop regions can be substructured into relatively smallbodies. For example:

Click on the Molecule Spec parameter block, then select Subset/NOT_IN_BODIES from the Parameters window.

Select Property Name/None

Select Substructure Method/Psi

Select a Residue Cut Frequency of 2.

Execute.

Example 3

Load a trajectory using DeCipher. Select MBOND from the list of mod-ules.

48 MBO(N)D


Select Bodies/Define from the lower menu bar.

Select Create.

Select Property Name/None.

Select Substructure Method/Psi.

Select a Residue Cut Rate of 3.

Execute.

Select Property Name/Kabsch_Sander (SHEET).

Select Substructure Method/Beta_Bridge.

Select Overlap Region Mode/Accept_New_Bodies.

Execute.

The whole protein is substructured into 3-residue bodies.

Figure 3

Preparing the model

MBO(N)D 49

Next (assuming that there are beta-sheet regions in the protein) this sub-structuring will result in creating 2- to 3-residue bodies across H-bond con-nected peptide chains.

Saving body definitions To save a body definition in a file, select the Bodies/Put command. Fill inthe Body Name parameter box with the name of the body you want to saveby entering the name or choosing it from the Body List value-aid. Enter afilename in the Filename parameter box or select one from the Files value-aid (the saved file is called filename.str). Select Execute.

Generating modes

Modes need to be generated for each defined body in your model that youwant to treat as flexible. Modes need not be generated for rigid bodies.

Accessing the tools Select the Modes/Generate command from the lower menu bar.

Specifying modes to gener-ate for a body

Specify the body for which you want to generate modes by entering itsname in the Body Name parameter box. Either:

© Type its name in the parameter box.

or:

© Choose its name from the Body List value-aid.

The modes for all bodies can be generated in one MBO(N)D calculation byentering “*” in the Body Name parameter box.

Choose the Generation Method that you want to use (see Choice of refer-ence coordinates and selection of modes for additional information).

Specify how modes are to be sorted by setting the Sort Modes By param-eter.

Modes are saved in a file. To specify the file’s name, enter it in the ModeFile Name parameter box.

Enter the number of modes to generate in the Number of Modes parameterbox. If the number of modes specified is less than the total number ofmodes possible, then the lowest N (in order of frequency) are saved.

Generating the modes Select Execute. This initiates a short MBO(N)D calculation that calculatesthe modes for the specified bodies.

50 MBO(N)D


Loading modes

After modes are generated (and stored in files) for the selected bodies inyour model, you need to load the modes back into the Insight program.Loading the modes automatically associates them with the correct bodies.

Modes have to be loaded for each body in your model that you wantMBO(N)D to treat as flexible.

Accessing the tools Select the Modes/Load command from the lower menu bar.

Loading modes for a body Specify the body whose modes you want to load by entering its name in theBody Name parameter box. Either:

© Enter its name in the parameter box.

or:

© Choose its name from the Body List value-aid.

Modes are contained in a file. To specify the file’s name, enter it in theModal File Name parameter box.

To load all modes, type “*”in the Body Name parameter box. AUTO willappear as Modal File Name. Note: this feature works only if you have usedAUTO as the Modal File Name during mode generation.

Specify the range or numbers of modes to load by filling in the ModesRange parameter box.

Select Execute.

Repeat this procedure for each body for which you want to load modes.

Animating modes

This is an optional step, which helps in visualizing the way the model willmove during subsequent dynamics simulations. Each desired body andmode is animated separately.

Accessing the tools Select the Modes/Animate command from the lower menu bar.

Animating a mode for abody

Specify the body whose mode(s) you want to animate by entering its namein the Body Name parameter box.

If modes were not already loaded with the Modes/Load command, specifythe mode file’s name by entering it in the Mode File Name parameter box.

Setting up the MBO(N)D simulation run

MBO(N)D 51

Specify the mode to be animated by filling in the Modes Value parameterbox. Choosing the mode from the value-aid animates the model automati-cally; that is, you do not need to select Execute.

You can change the relative magnitude of the displacements during anima-tion by changing the Animation Scale. The higher the number you enter,the larger the amplitude of the modal displacements.

Select Execute to animate the model (if it is not already moving).


Run conditions for dynamics simulations can be quite complicated. Youuse several parameter blocks to fully set up the run. The job is not actuallysubmitted for running until you execute the MBOND_Run/MBOND_Run command.

Thus you can modify your setup at any point before submitting the job. Youmay, if you want, set up the run within the Insight interface, save the inputfiles, edit the command input file if required, and then submit the job instandalone mode.

In addition, you can set up more stages than you may actually want to usein a given simulation. The setup stages are not actually incorporated intothe command input file unless you specify them in the MBOND_Run/MBOND_Run parameter block.

Specifying how to handle nonbond interactions

See the CHARMm documentation and Forcefield-Based Simulations foradditional information on handling nonbond interactions.

Accessing the tools Select the SetUp/Nonbond command from the lower menu bar.

Specifying nonbond meth-ods

Set the update frequency, cutoff value, etc., by entering numbers in the rel-evant parameter boxes.

Specify how to handle long-range nonbond interactions by choosing aNonbond Smoothing method.

Specify the treatment of electrostatic interactions by choosing a DielectricMethod.

52 MBO(N)D


Select Execute.

The Miscellaneous Mean Field Potential (MMFP)

The MMFP command activates the Miscellaneous Mean Field Potentialwithin CHARMm. MMFP applies spherical restraining potentials to thespecified region of a molecule. The restraining potentials are then used inall energy calculations.

Accessing the tools Select the SetUp/MMFP command from the lower menu bar.

Specifying MMFP methods To specify the use of MMFP during CHARMm simulations, click the UseMMFP toggle.

Set the origin of the restraining potential by entering custom coordinates orby clicking Use CM to specify that the center of mass of the specifiedatoms will be the origin. Force specifies the amplitude of the restrainingpotential.

Select Execute.

Constant VELocity method (CVEL)

The CVEL command enables the constant velocity method withinMBOND. The constant velocity method, in conjunction with NOE restrain-ing potentials, creates a “spring” between two atoms.

Accessing the tools Select the SetUp/CVEL command from the lower menu bar.

CVEL methods To specify the use of CVEL during CHARMm simulations, click the UseMMFP toggle.

Specify the two atoms to be used (Atom1 Spec, Atom2 Spec), and themagnitude of the constant velocity vector (Velocity). The vector pointsfrom atom 1 to 2.

Select Execute.

Setting up the dynamics calculation

The dynamics job is set up in distinct heating, equilibration, and data-col-lection stages (see Stages and duration of dynamics simulation). You need


MBO(N)D 53

to specify the type of run (constant energy or constant temperature) and thefrequency of data output.

Also see the CHARMm documentation and Forcefield-Based Simulationsfor additional information on the stages and types of dynamics runs.

Constant-temperature dynamics, equilibration stage

During the equilibration stage, dynamics is run until the system is thermo-dynamically stable under the conditions to be used during the later data-collection stage.

Accessing the tools Select the SetUp/Dynamics command from the lower menu bar.

Selecting run conditions To specify a constant-temperature run, set the Dynamics Ensemble toNVT.

If a heating phase is needed, set the Temperature Control parameter toHeat.

Alternatively, to specify an equilibration stage, set the Temperature Con-trol parameter to Equilibrate. This periodically rescales the velocities ofthe system to the desired temperature.

Set the time step and other parameters by entering numbers in the relevantparameter boxes.

If you want to use bond constraints, toggle the Bond_Constraints param-eter on.

Select Execute to set up a constant-temperature equilibration stage for yourdynamics run.

Constant-temperature dynamics, atomistic data-collection stage

Set up this stage if you want to include a constant-temperature data-collec-tion stage of MBO(N)D dynamics.


Selecting run conditions To specify a constant-temperature run, set the Dynamics Ensemble toNVT.

Set the Temperature Control parameter to Simulate.

NVT dynamics is performed by coupling to a heat bath, which scales thevelocities every step.

54 MBO(N)D




Select Execute to set up a constant-temperature data-collection (atomistic)stage for your dynamics run.

Constant-energy dynamics, data collection

Set up this stage if you want to include a constant-energy data-collectionstage in your MBO(N)D run.


Selecting run conditions To specify a constant-energy run, set the Dynamics Ensemble to NVE.



Select Execute to set up a constant-energy data-collection stage for yourdynamics run.

Output frequencies

Accessing the tools Select the SetUp/Files command from the lower menu bar.

Specifying output frequen-cies

Specify values for the frequencies with which to output various files byentering numbers in the relevant parameter boxes.

Select Execute.

Stream files

The Stream_Files command defines input files that will be called from themain CHARMm input file. All files selected using the STREAM FILEScommand will be processed by CHARMm after it has loaded all topologyand parameter data, but before any dynamics or minimizations have begun.The stream files can contain any valid CHARMm keywords.

Accessing the tools Select the SetUp/Stream_Files command from the lower menu bar.

Specifying stream files Specify the File Control action and the File Name.


MBO(N)D 55

Select Execute.

Setting up the parameter mode

MBO(N)D can run in either PSF or RTF mode. The default mode is to runin PSF mode, where Insight performs atom typing and generates a PSF forthe MSI forcefield that is read by MBO(N)D. The RTF mode allows you touse alternative forcefields. By changing the parameter mode to RTF, youcan select RTF files from the value-aid and have MBO(N)D generate theprotein structure information from the parameter files. By default the Har-vard Param19 and Param22 topology files are in the $BIOSYM/gifts/mbond directory. To use either of these forcefields you need to set the envi-ronment variable MBOND_GIFTS to point to the current location. Formore detailed information see the README file in that directory.

Accessing the tools Select the SetUp/Parameter_Mode command from the lower menu bar.

MTS integrator

The MTS_Integrator command enables the Multiple Time Scale integra-tor during an MBOND simulation. The MTS integrator recalculates forceson different regions of the molecule using different timesteps. In MBOND,only nonbonded forces are updated in this way.

Accessing the tools Select the SetUp/MTS_Integrator command from the lower menu bar.

Specifying MTS Specify the timescale multiples (a comma-delimited list of up to four inte-gers greater than 1) for the long timescale motions. If Auto (default) isspecified, MBOND will automatically determine the number of timestepmultiples and their values.

Now specify the linear scale parameter, which determines the scaling ofmasses as the distance between two interacting regions increases (for moreinformation, see the online help text).

If you wish a cutoff value for mass scaling, select Use_Threshold andspecify the value under Distance.

You can specify a scaling factor determining the update frequency of non-bonded forces for heavier bodies or atoms. Select Calibrate and enter thefactor under Calibration Value.

56 MBO(N)D


Setting up the background job

Use of the Background_Job pulldown is optional. If it is not used, thedefault is to run all jobs on the local host in Cont_Insight mode (see theBackground_Job/Setup_Bkgd_Job command). If you prefer this mode,you do not need to read the remainder of this subsection.

When the Background_Job/Setup_Bkgd_Job command is used, thebackground job list shows only those background jobs that are run from thecurrent module and can be run on a remote host. If the module contains onlyone job, the parameter is automatically filled in. The list of hosts showsonly those hosts that are associated with that background job in thebackground_job_hosts file at your site. It is possible for you to specify aremote host that is unavailable (off line, for instance) or for which you haveno login account.

Use the Background_Job/Control_Background_Job command to coor-dinate running background jobs by detaching selected jobs from or attach-ing them to Insight. In addition, you can use this command to specify theinterval for invoking a task specific to a particular background job for pro-cessing its output.

Every background job submitted via the generic background utility isassigned a job number. This number is displayed in the information areawhen the job is submitted (e.g., Starting Module backgroundjob ... as job 1). You should note the job number when the job issubmitted, since it can be used later to check on the job’s completion statusor kill the job.

The Setup_Bkgd_Job command does not actually run the command; itsimply records your host and execution mode preferences. The default hostis Local. Your selected host and Execution_Mode are used for any subse-quent background jobs for the duration of the Insight session. When youstart up a new session, all background job parameters are set to their defaultvalues.

The Execution_Mode parameter allows you to run a background job con-currently (Cont_Insight) or interactively (Wait_For_Job) or to simplycreate the necessary command files to submit the job, but not actually exe-cute them (Cmd_File_Only).

The Send_Mail parameter allows you to have the system send you an elec-tronic mail message upon completion of the background job. This parame-ter is not active if Execution_Mode is set to Wait_For_Job. You may find


MBO(N)D 57

this option useful when running long jobs where you exit the Insight pro-gram before the job completes.

The Save_Cmd_Files parameter allows you to save the command file usedto submit the background job (bkgd_job_run_name#.csh). Otherwise thisfile is deleted when the job completes. This parameter is not active whenExecution_Mode is set to Cmd_File_Only.

All background jobs return a completion status. The completion status is aninteger code that indicates success, failure, and/or reason for failure of thejob. The status code is always displayed when you are notified that the jobhas completed.

If you consistently want to send background jobs to another host, you canmodify your personal Insight startup file to invoke Setup_Bkgd_Job foreach module/background job(s) that you want to automatically assign. Notethat you must first change to the appropriate module in which the back-ground job’s interface is found before using Setup_Bkgd_Job to set a pref-erence for that module’s background jobs.

The Completion_Window parameter can be used to prevent the notifica-tion window from appearing when the background job completes. Thedefault value is on.

Support for the network queuing system (NQS) is now available in theBackground_Job/Setup_Bkgd_Job command.

For the Insight interface to present parameter defaults and a value-aid con-taining available queues, and to correctly formulate an NQS command,your NQS queue environment information must be provided to the Insightprogram. The Background_Job_Hosts file contains the NQS queue infor-mation, or you may enter the required information directly using theBackground_Job/Setup_Bkgd_Job command.

Based on the parameter values provided in the Background_Job/Setup_Bkgd_Job command for Queued Submission_Mode, the Insight back-ground job mechanism formulates a standard NQS command and starts aprocess to execute it. It is assumed that the NQS command constructed bythe Insight program functions with your NQS configuration.

58 MBO(N)D


Running the MBO(N)D simulation

Submitting the MBO(N)D job

Accessing the tools Select the MBond_Run/MBond_Run command from the lower menu bar.

Putting your job specifica-tion together

The dynamics stages that you specified by executing commands in theSetUp pulldown are not actually incorporated into a command input fileuntil you specify the stages in the MBond_Run/MBond_Run parameterblock.

Thus you can specify stages to include in certain simulations but not in oth-ers. For example, you may want or need to run some stages as separate jobs,or you may need to resume a job that was interrupted during one of the laterstages (and would therefore not need to use any preceding stages).

Specifying which stages touse

Toggle on any combination of Heat, Equilibrate, and Simulate to selectthe simulation stages to include in the actual run.

Set Dynamics Ensemble to NVE (constant energy) or NVT (constant tem-perature).

Restarting from a previousrun

To begin the simulation from a previously generated MBO(N)D orCHARMm restart file, toggle the Use_Restart_File parameter on. Thenenter the name of the restart file in the Restart Read File parameter box.

Specifying run conditions Choose the desired Interaction Method to specify how the intra-bodyenergy and forces are calculated.

© Full_Forcefield indicates that the full, nonlinear forces are used. Thisis the MBOND ATOM option in standalone mode.

© Modal_Stiffness indicates that substructuring is taken into accountwhen calculating energy, etc. This is the MBOND ON option in standa-lone mode.

Choose the desired MTS_Integrator (Integration algorithms). If youchoose the Multiple_Time_Scale method, then enter a value for the MTS_Multiples under the Setup/MTS_Integrator command.

Specify the COM Stopping Frequency. The COM Stopping Frequencyparameter indicates the step frequency for stopping the rotation and trans-lation of the model during dynamics. This operation is done automatically

Running the MBO(N)D simulation

MBO(N)D 59

after any heating. This is the NTRFRQ parameter in standaloneCHARMm.

Starting the run Select Execute.

Monitoring a background job

The Background_Job/Completion_Status command has three modes ofoperation. The One_Job option displays a brief message indicating if aspecific job has completed. The message is displayed in the informationarea of the screen. Certain background jobs generate a status file containingadditional information while they are running. If this additional statusinformation is available, it is displayed in the textport. If All_Jobs is cho-sen, the job number, job name, run name, status code, and job status are dis-played in the textport for every job submitted during the current Insightsession. The Look_Up_Status option is used to look up the meaning of areturn status code.

The Report_Mode parameter is used to indicate what information youwould like the command to return: status of one job, status of all jobs, orthe meaning of a return status code from a particular job.

The Job_Number parameter becomes active when One_Job is selected. Itis used to specify the background job that you want to monitor.

The Background_Job and Status parameters become active when Look_Up_Status is chosen. They are used to specify a status code that you wantto look up.

The Kill_Bkgd_Job command is used to stop execution of a backgroundjob by killing its process and, optionally, deleting its output files.

The Job_Number parameter is used to specify which background job tokill. A value-aid containing a list of all currently running background jobsis provided.

If the Save_Output parameter is toggled on, then all output files generatedby the background job are saved when the job is killed. The default valueof this parameter is off, meaning that all output files are deleted.

60 MBO(N)D


MBO(N)D 61

5 Command Summary—Insight

MBO(N)D is accessed in the Insight environment by choosing MBONDfrom the Module pulldown (which is accessed by clicking the MSI logo).The MBOND module contains several pulldowns (in addition to the corepulldowns on the top menu bar), which appear on the lower menu bar. Theyare: Bodies, Modes, SetUp, MBOND_Run, Background_Job, andPseudo_Atom. Each pulldown gives access to several related commands.The SetUp pulldown, for example, contains a set of commands used in set-ting up an MBO(N)D calculation: Dynamics, NonBond, and Files aresome of the items to be found under Setup.

What the commands in these pulldowns do is summarized briefly below.For more detailed explanations of individual commands, refer to the on-line help facility (by clicking the help icon, which is the button containinga question mark, on the left side of the main Insight window). For informa-tion on how to use these commands, see Chapter 4, Methodology—Insight.

Bodies pulldown

The Bodies pulldown contains commands that allow for the creation andmanipulation of bodies. A body is a set of atoms that are treated as a singleunit during the MBO(N)D simulation.

The Bodies/Get command is used to read in sets of atoms from a file todefine bodies. The file contains only the SUBSTR section of MBO(N)Dinput with the atom selections described using the CHARMm SELECTBYNUm commands.

The Bodies/Put command is used to write a set of bodies to a file. The filecontains only the SUBSTR section of MBO(N)D input with the atomselections described using the CHARMm SELECT BYNUm commands.

The Bodies/Define command is used to specify sets of atoms that are to betreated as bodies. Within the Define command the Molecule Spec param-eter box and the Property Name and Substructure Method value-aids are

62 MBO(N)D

5. Command Summary—Insight

powerful tools that allow you to substructure your molecule using a widevariety of methods.Use Molecule Spec to select large portions of the mol-ecule, then select Property and Substructure Method options to furtherdefine bodies.

The Bodies/Edit command is used to modify the atoms and colors that con-stitute the body. Atoms may be added or deleted and are described in thesame way as in the Bodies/Define command.

The Bodies/Delete command is used to delete a single body or set of bodiesfrom the model.

The Bodies/Color command is used to color the atoms within a body usingthe color specified when the body was defined. This is useful for visualiz-ing the atoms in particular bodies when the model coloring has been mod-ified. You can choose to color atoms which have not been assigned to abody by selecting Subset/NOT_IN_BODY from the Parameters window.

The Bodies/List command is used to output information about previouslydefined bodies. This includes the atoms, color, and modes associated witheach body.

Modes pulldown

The Modes pulldown contains commands that allow association of modesto a body or the animation of these modes for a body. The modes are gen-erated by MBO(N)D and stored in a user-specified file on disk.

The Modes/Load command is used to associate a set of modes from a userspecified file with a body. These modes are then loaded during subsequentMBO(N)D dynamics simulations.

The Modes/Generate command is used to create a set of modes for thespecified body. This starts an MBO(N)D simulation that only generatesmodes and does not include dynamics.

The Modes/Animate command is used to visualize a mode for a body. Thiscreates a temporary animation of the body using the mode as a displace-ment vector from the nominal coordinates stored in the specified modesfile. This is useful for visualizing the modes before associating them for thesimulation.

SetUp pulldown

MBO(N)D 63

SetUp pulldown

The SetUp pulldown contains commands that allow modification of thedefault CHARMm parameters.

The SetUp/Minimize command is used to set up a minimization run.

The SetUp/Dynamics command is used to modify the parameters for thevarious dynamics stages, including heating, equilibration, and simulation.

The SetUp/NonBond command is used to modify the parameters used incalculating nonbond interactions during a simulation.

The SetUp/Files command is used to control how often various informa-tion is output, including coordinates, velocities, energies, and restart infor-mation.

The SetUp/Parameter_Mode command is used to control runs in PSF orRTF mode and to select parameter files for RTF mode.

The SetUp/MTS_Integrator command is used to modify parameters usedin the MBO(N)D multiple time step integrator.

MBOND_Run pulldown

The MBOND_Run pulldown contains commands that initiate anMBO(N)D run.

The MBOND_Run/Minimize command is used to start a minimizationjob.

The MBOND_Run/MBOND_Run command is used to start anMBO(N)D dynamics run.

Background_Job pulldown

The Background_Job/Setup_Bkgd_Job command allows you to set upthe execution mode and select the host upon which to run a job. This com-mand is also used to control the notification method for background jobcompletion and cleanup options.

64 MBO(N)D

5. Command Summary—Insight

The Background_Job/Control_Bkgd_Job command allows you to coor-dinate running background jobs by detaching selected background jobsfrom or attaching them to the current Insight session. In addition, this com-mand allows you to specify the interval for invoking a task specific to a par-ticular background job for processing its output.

The Background_Job/Completion_Status command allows you to mon-itor and evaluate the completion status of one or all background jobs. Inaddition, this command can be used to look up the meaning of a return sta-tus code.

The Background_Job/Kill_Bkgd_Job command is used to terminate exe-cution of a background job that was submitted during the current Insightsession.

MBO(N)D 65

6 Command Summary—StandaloneMode

The MBO(N)D commands are documented in full in Appendix D,Commands—Standalone Mode, where the commands are listed in alpha-betical order. Below is a list of the commands according to their functions,followed by a brief description and the page on which the complete descrip-tion starts.

MBO(N)D-specific keywords

MBOND

Set up the MBO(N)D system

SUBStructure

Define bodies (substructuring)

MODES

Specify modes for flexible bodies

GENERATE

Calculate modes for the specified body

MTS integrator

Specify parameters for multiple time scale Lobatto integrator

66 MBO(N)D

6. Command Summary—Standalone Mode

MBO(N)D dynamics keywords

DYNAMICS

Additions to the CHARMm DYNAMICS command

MBO(N)D 67

7 Methodology—Standalone Mode

Running an MBO(N)D simulation in standalone mode

Input files required

Command script file Assuming that you have a properly prepared input script file named run_name.inp and an executable named mbond.exe, the simplest way to submita run is to enter at the UNIX prompt:

>/pathname/mbond.exe < run_name.inp > run_name.out &

Alternatively, you can put these commands into a file like the one below:

#comments#comments#comments/pathname/mbond.exe < $1.inp > $1.out

If the command file is called run.com, and the name of the simulation isrun_name, you can enter at the UNIX prompt:

>run.com run_name &

to submit the simulation.

Other input files The other input files for an MBO(N)D CHARMm simulation are:

© CHARMm RTF file.

© CHARMm parameter file.

© CHARMm PSF file (optional).

© CHARMm coordinate file in .crd or .pdb format.

© Stream (.str) file containing MBO(N)D substructuring information.

© Modes files for each flexible body defined in the .str file (optional).

68 MBO(N)D

7. Methodology—Standalone Mode

© CHARMm .rst file (from an atomistic equilibration run, an MBO(N)Dequilibration run, or an MBO(N)D production run; optional).

General MBO(N)D procedure

Invoking MBO(N)D Substructured molecular dynamics is invoked by using the MBONDoption of the regular CHARMm DYNAmics command. This enables sev-eral keywords particular to MBO(N)D and disables some that are not sup-ported. In general, however, all the standard DYNAmics keywords aresupported, unless specifically mentioned here.

See the CHARMm documentation for details on the DYNAmics com-mand.

Bodies and modes Bodies must have been defined prior to invoking MBO(N)D dynamics (seeSUBStructure). If no modes have been loaded (or generated) for the bodies,they are assumed to be rigid.

Temperature control Only velocity scaling is supported for heating and equilibration protocols.However, the initial velocities may be assigned using any of the CHARMmoptions (including using a restart file). The thermostat that is available is asimple Berendsen method.

Printing of the overall temperature and the temperature of the body and ato-mistic regions can be separately controlled by the TFRQ option in theDYNAmics command. In addition, this reports the individual kineticenergy of each body.

Simulation stages A typical protocol is to heat a system using an atomistic simulation, thenequilibrate it and generate modes. When the switch is made to a substruc-tured simulation, the system needs to be equilibrated once more before thedata-collection stage of dynamics can begin.

Multiple time scales Multiple time scales are supported in MBO(N)D. As usual, the MTS key-word must precede dynamics simulation. The MASS and DISTANCEkeywords must be specified. They segregate nonbond interaction updatingby combined mass/distance criterion (Multiple time scales). You can spec-ify the number of stages for the MTS via the ratios keyword or allow it tobe computed automatically.

The following CHARMm features are not supported in multibody simula-tions: SHAKE constraints (although bond length constraints between bod-ies and particles are supported with the HINGE BOND command),

Specific commands

MBO(N)D 69

constant-pressure dynamics, Nosé–Hoover temperature control, Langevindynamics.

Integrators The integrators that MBO(N)D does support are Lobatto and MTS Lobatto.The leapfrog and 4D Verlet algorithms cannot be used.

General outline of command input file

The most important elements in an MBO(N)D input script are:

1. Read in the topology and parameter files.

2. Read in the CHARMm .psf (protein structure file), which contains thelist of atoms in the system being simulated and their connectivities.Alternatively, generate the structure (and the .psf file) withinCHARMm.

3. Read in the starting coordinates, either in the CHARMm .crd or .pdbformats (coordinates only) or from a CHARMm .rst file (restart file,which contains both coordinates and velocities).

4. Specify the desired substructuring for your MBO(N)D run.

5. If bodies are flexible, generate or load (from file) the mode shape vec-tors to be used for each body.

6. Initiate MBO(N)D dynamics simulation using the DYNAMICSMBOND command.

Specific commands

Except for MBO(N)D-specific commands, which are documented inAppendix D, Commands—Standalone Mode, please see the CHARMmPrinciples book and other html files for detailed documentation.

Control commands © SET string1 string2—Define string1 as string2, exactly as it appears.

The SET command is helpful when files with long pathnames are usedmore than once. It is also useful for defining and resetting a a parameterthat is used often in the script.

© bomlev #—Set the level of error severity that causes an MBO(N)DCHARMm job to terminate. # is usually set to -1.

70 MBO(N)D


CHARMm input com-mands

© OPEN READ UNIT # FORM/UNFORM—Open a file of unit # forreading.

© READ RTF—Read a topology file.

© READ PARA—Read a parameter file.

© READ PSF—Read the CHARMm PSF file.

© READ COOR—Read a set of coordinates in CHARMm .crd format.

© STREAM filename —Read in a file containing information that is usedrepeatedly over many runs, such as substructuring information.

Nonbonds © NBOND options—A CHARMm command that allows you to set var-ious nonbond interaction options, such as options for the update of thenonbond interaction list and options that determine how the van derWaals and Coulombic interactions are evaluated. These options aredescribed more fully in the CHARMm Dictionary (online).

MBO(N)D-specific com-mands

© MBOND ATOM—Control how interactions within flexible bodies arecomputed. If MBOND ATOM is activated, the intrabody interactionsare calculated using the CHARMm forcefield. If MBOND ATOM isnot invoked, then the intrabody interactions are calculated using themodal stiffness terms associated with the modes.

© MBOND NBODY nb—Activate MBO(N)D to receive substructuringand modal information. nb is the number of bodies. (See also SUBStruc-ture.)

© SUBSTRUCTURE—Identify collections of atoms to group into bod-ies (SUBStructure). Identify the body with the CHARMm SELEC-TION commands (see CHARMm Dictionary).

© MODES—Activate the MBO(N)D capability to read in modal infor-mation through mode files (MODES).

© LOAD—Load the information from the modal file (MODES).

© USEM—Given a number of modes loaded into the system, USEMallows you to use a subset of them (MODES).

© GENERATE—Calculate NMODE modes for the specified body.

© PED—The MBO(N)D version of the CHARMm facility to be used foranalyzing body-based modes. Modes must have been already loadedand must be vacuum modes.

Specific commands

MBO(N)D 71

The sections starting with MBOND NBODY, MODES, and SUBSTRUC-TURE must be terminated with an END statement.

Dynamics commands © DYNAMICS MBOND (RE)START—This command is analogous tothe usual CHARMm command (see CHARMm Dictionary), except forthe MBO(N)D keywords, which can be used to invoke the MBO(N)Ddynamics program (see also DYNAMICS).

© LOBATTO—Invoke the Lobatto integrator.

© MTS—This command, when it appears within an MBOND block,invokes the MBO(N)D multiple time scale integrator.

© MBPRLEV—Determine the extent of MBO(N)D-relevant informa-tion printed out during the run. A value of -1 prints out the least infor-mation, and a value of 9 prints out the maximum amount of information.Use values above -1 only when debugging (see DYNAMICS).

© VECFRQ—Determine the frequency with which MBO(N)D vectorinformation is output. As with MBPRLEV, a value different from 0 isused mainly for debugging purposes.

Most other dynamics options and commands present for regular CHARMmare available for MBOND/CHARMm. Please consult the CHARMm doc-umentation for the relevant descriptions.

Output commands © OPEN WRITE UNIT #—Open a file of unit # for writing.

72 MBO(N)D


MBO(N)D 73

8 Tutorials

This chapter describes several lessons for the use of MBO(N)D, the body-based molecular dynamics software.

Introduction and overview of Pilot online tutorials

Several tutorials are now available online for use with the Pilot interface.To access the online tutorials for MBOND, click the mortarboard icon inthe Insight II interface.

Then, from the Open Tutorial window, select MBOND tutorials, andchoose from the list of available lessons:

© Lesson 1: Using the MBO(N)D Software

© Lesson 2: Using Sidechain Vector Analysis from the SemiautomatedPanel

© Lesson 3: Pseudodihedral Analysis and Mode Generation

© Lesson 4: Pseudodihedral Analysis and Crystal Clusters

© Lesson 5: Beta-bridge Substructuring

© Lesson 6: Ligand Pulling

You can access the Open Tutorial window at any time by clicking theOpen File button in the lower left corner of the Pilot window.

For a more complete description of Pilot and its use, click the on-screenhelp button in the Pilot interface or refer to the Introduction to Insight IIchapter in the Insight II manual.

74 MBO(N)D

8. Tutorials

MBO(N)D 75

A References

Amadei, A.; Linssen, A. B. M.; Berendsen, H. J. C. Proteins, 17, 412(1993).

Bahar, I.; Atilgan, A. R.; Erman; B. Folding & Design, 2, 173 (1997).

Benfield, W. A.; Hruda, R. F. AIAA Journal, 9, 1255 (1971).

Bodley, C. S.; Devers, A. D.; Park, A. C.; Frisch, H. P. NASA TechnicalPaper 1219 (1978).

Brooks, B. R.; Bruccoleri, R. E.; Olafson, B. D.; States, D. J.; Swami-nathan, S.; Karplus, M. J. Comp. Chem., 4, 187–217 (1983).

Chun, H. M.; Turner, J. D.; and Frisch, H. P. Paper AAS-89-457, AAS/AIAA Conference, Stowe, Vermont (1987).

Chun, H. M.; Turner, J. D.; Frisch, H. P. Paper AAS-91-455 AAS/AIAAAstrodynamics Specialist Conference, Durango, Colorado (1991).

Craig, R. R., Jr. Shock Vib. Digest, 9, 3 (1977).

Ding, H.-Q.; Karasawa, N.; Goddard III, W. A. J. Chem. Phys., 97, 4309(1992).

Durand, P.; Trinquier, G.,; Sanejouand, Y.-H. Biopolymers, 34 (1994).

Greengard, L.; Rokhlin, V. J. Comp. Phys., 73, 325 (1987).

Greengard, L.; Rokhlin, V. Chem. Scr., 29A, 139 (1989).

Hao, M.-H.; Harvey, S. C. Biopolymers, 32, 1393 (1992).

Hao, M.-H.; Scheraga, H. A. Biopolymers, 34, 321–335 (1994).

Horiuchi, T.; Go, N. Proteins, 10, 105 (1991).

Ichiye, T.; Karplus, M. Proteins, 11, 205 (1991).

Lee, A. Y.; Tsuha, W. S. J. Guid. Control. Dyn., 17, 69 (1994).

Levy, R. M.; Karplus, M.; Kushick, J.; Perahia, D. Macromolecules, 17,1370 (1984).

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A. References

Mizuguchi, K.; Kidera, A.; Go, N. Proteins, 18, 34 (1994).

Momany, F. A.; Rone, R. J. Comp. Chem., 13, 888–900 (1992).

Space, B.; Rabitz, H.; Askar, A. J. Chem. Phys., 99, 9070 (1993).

Tirion, M.M., Phys. Rev. Letts., 77, 1905 (1996).

Tuckerman, M.; Berne, B. J.; Martyna, G. J. J. Chem. Phys., 97, 1990–2001(1992).

Turner, J. D.; Weiner, P. K.; Chun, H. M.; Lupi, V.; Gallion, S.; Singh, U.C. Chapt. 24 in Computer Simulation of Biomolecular Systems: Theo-retical and Experimental Applications, 2, Gunsteren, W. F.; Weiner, P.K.; Wilkinson, A. J., Eds., ESCOM, Leiden (1993).

MBO(N)D 77

B File Formats

Input files

© CHARMm RTF file.

© CHARMm parameter file.

© CHARMm PSF file.

© CHARMm coordinate file in .crd format.

© CHARMm .rst file (if restarting from an atomistic equilibration run, anMBO(N)D equilibration run, or an MBO(N)D data-collection run).

MBO(N)D-specific files

Only one new file format has been introduced to support multi-bodydynamics (the ASCII mode file). All the other relevant file formats are usedas standard CHARMm files.

The format deviates from the CHARMm VIBRAN format in two ways:

© It contains additional information: nominal coordinates and the modalstiffness matrix.

© The modes are stored in order of increasing frequency from the lowestfrequency up. The six global translation/rotation modes are notincluded.

Properties such as delocalization may also be stored in this file.

78 MBO(N)D

B. File Formats

The file format is:

TitleHeaderNominal CoordinatesModal Stiffness Matrix (Upper Triangular)Properties

Frequencies (always)Delocalization (if computed)Other (none yet defined)

Mode1: eigenvector (x1,y1,z1, x2,y2,z …)Mode2: ...

...

The format is, in fact, rather general, allowing multiple mode sets (includ-ing multiple sets of nominal coordinates etc.) to be stored in one file. Ingeneral however, each body has one file with a single set of modes stored.

The header contains the following data:

Version numberMode generation methodNumber of atoms in this bodyNumber of nominal coordinate setsNumber of stiffness matrix filesNumber of distinct properties storedNumber of modes in the fileSort order of the modes

MBO(N)D 79

C Miscellaneous

Technical notes

Memory requirements andlimitations

To perform an MBO(N)D calculation, Insight runs an MBOND executable.

The following limits apply:

The last item applies only when you run with bond constraints betweenbodies (i.e., using the keyword HINGE BOND). It means that there can beat most two loops when traversing between bodies (so that, for example, aproline ring that is entirely within a body does not count).

If this limit is encountered, an error message is printed. The workaround isto run with HINGe OFF.

The executable can be run in standalone mode by entering at the commandline the full name of the executable:

> mbond.exe < input > output [&]

MBOND executables’ limits Large

Maximum number of bodies that can be defined. 1,000

Maximum number of atoms that are not in bodies. 5,000

Maximum number of atoms that are in bodies. 25,000

Largest number of atoms in a body. 500

Maximum number of modes per body. 20

Maximum number of topological loops. 2

80 MBO(N)D

C. Miscellaneous

Unsupported CHARMm facilities

These CHARMm facilities are not compiled with, and therefore not avail-able in, the current MBOND/CHARMm implementation:

Free energy perturbation (BLOCK, TSM)Quantum and Gamess interfacesReplica code (support for MCSS)AspenerEispack diagonalizationFast multipole methodsFourD minimization and dynamicsMolecular vibrational analysis (MOLVIB)RISMFMARXNCORNIH Shapes descriptor codeTruncated Newton minimizerPath and Travel facilitiesZ table supportGraphicsExplicit parallelizationVector supportPBOUNDCRYSTAL

These CHARMm facilities are compiled but not currently supported withthe MBO(N)D/CHARMm implementation:

PERTDIMBIMAGES

MBO(N)D 81

D Commands—Standalone Mode

Documentation format

Capitalized, BOLD words are keywords that must be specified as is. How-ever, if the word is partially capitalized, it may be abbreviated to the capi-talized part. Italic words are to be replaced by a corresponding data entry.Anything enclosed in square brackets [ ] is optional. If several things arecontained within square brackets, you may optionally choose one of them.Anything enclosed in curly braces { } specifies that a selection must bemade from the choices within. The syntactic entities that appear as an argu-ment to repeat (indicated by ellipses … ) may be repeated any number(including zero) of times.

CHARMm command lines

General format of MBO(N)D as single-line command

MBOND { [ON ] }{ [OFF ] }{ [CLEAr ] }{ [STATus { [SHORt } }

{ [LONG [BODY char*4] ] }{ [VLONg [BODY char*4] ] }

{ [ATOM]}

82 MBO(N)D

D. Commands—Standalone Mode

General format of MBO(N)D command block

MBOND [NBODY integer]SUBStructure

BODY char*4 SELEct (...) END [SHOW]HINGE { [BOND [SELEct (...) END]]} [ANGLe] [DIHEdral] [OFF]{ [HBONd] }

ENDMODEs { [KEEP ] } [NMODe integer]

{ [DELEte] }LOAD char*4 {[NMODe integer] } UNIT integer

{[MODE integer THRU integer]} [SHOW] [NOVEC][FORMatted/UNFORmatted]

UNLOad char*4USEM char*4 {[NMODe integer] }

{[MODE integer THRU integer]}PED char*4 {[NMODe integer]} {[MODE integer THRU integer]}

[real] [TOL real]GENErate char*4 [NMODe integer] [SHOW]

MINI minimiz_specDIAG method_specWRITE {[NMODe integer] } UNIT integer

{[MODE integer THRU integer]}[FORMatted/UNFOrmatted]

ENDENDMTS

MASS [CALIbration real]DISTance

LINEar aCUTOn R

ENDRATIos integer integer …CLEARMAXStep

ENDEND

Detailed command descriptions

MBO(N)D 83


CVEL

A constant velocity method has been developed for use with DYNA. Thismethod works only with LEAP (in CHARMm) and LOBATTO (inMBO(N)D) integrators.

The CVEL command may be used to run simulations similar to atomicforce microscopy. The constant velocity method, therefore, is used in con-junction with the NOE facility used to apply a “spring” between two atoms.

A constant velocity for an atom is entered via CVEL in CHARMM syntax:

CVELocity <real> SELE <atom1> END SELE <atom2> END

where <real> = constant velocity in Angstroms/ps. The constant velocityvector and direction are defined from <SELE atom1> to <SELE atom2>.The position of <SELE atom2>, typically a dummy atom, is moved to theposition <SELE atom1> + 0.0001Å along the vector (because CHARMMdoes not like duplicate coordinates). <SELE atom2> then traverses alongthe vector at the constant velocity rate.

See tutorial 6 for details of how this command is used to simulate atomicforce microscopy experiments.

DYNAMICS

Please see the HTML-hypertext CHARMm documentation for completedescriptions of the DYNAMICS command. The MBO(N)D CHARMminterface supports most of the regular CHARMm DYNAmics options. Thebasic START, RESTART, NSTEP, and TIMESTEP are all implemented.

MBO(N)D-specific,DYNAMICS keywords

With the exception of NTRFRQ, only keywords specific to MBO(N)D aredocumented here.

NTRFRQ, which determines the frequency for stopping the rotation andtranslation of the molecule during dynamics, is not MBO(N)D specific, butit deserves special comment here. Due to the fact that the Lobatto integratorused to integrate multibody equations of motion is not symplectic, theconservation of linear and angular momenta are not as good as in atomisticdynamics using symplectic integrators (e.g., Verlet). Therefore in long

84 MBO(N)D


dynamics runs it is necessary to use a non-zero value for this parameter toperiodically (e.g., every 1ps) stop center of mass motion.

MBPLev = -1No printout from within MBO(N)D, only the data passed to CHARMm areprinted out (every NPRInt time steps).

MBPlev = 0Basic printout from within MBO(N)D—modal and kinetic energy for eachbody, linear and angular momentum for each body.

MBPlev = 1The above plus convergence rate during initial fitting.

MBPlev = 2The above plus all initial input data for each body and particle.

MBPlev = 3Full printout from within MBO(N)D.

MBPlev = 9Extended (debugging) printout from within MBO(N)D—the above plus allsizes for the multibody dynamics arrays, completedescription of the initial data, modal amplitudes, bodyvelocities, and angular velocities.

ATOM If this is not specified (or has not been previously), the linear forceapproximation is used within bodies. If specified, thefull force computation is performed.

Note

Frequency specifications

Supported:INBFrq NPRInt NSAVC NSAVV ISVFRQ IEQFrq NTRFrq IHTFrq IPRFrq

Not supported:IHBFrq ILBFrq

Unit specifications

Supported:IUNCrd IUNRea IUNVel IUNWri KUNIt

Not supported:CRAShu BACKup

Temperature specification

Supported:FINAlt FIRStt TEMInc TWINDH TWINDL TSTRuc ICHEcw

Not supported:TBATh

Options specification The behavior is equivalent to ISCVEL = 0; IASORS = 0 (i.e., always scaleduring heating and equilibration using a single scale factor).

Supported:IASVel ISCVel ISEEd ISCAle SCALe

Please see the CHARMm documentation for complete descriptions ofthe DYNAMICS keywords mentioned below. “Supported” meansthey can be used in MBO(N)D calculations.


MBO(N)D 85

Not supported:NDEGf RBUFfer AVERage ECHEck TOL (TOL is used for the tolerancein velocity Verlet convergence.)

Constant-pressure and -temperature keywords

From the constant-pressure and -temperature (CPT) options, only theTCONST option with the Berendsen thermostat is currently supported.

Supported:TCONst TCOUpling TREFerence

Not supported:PCONst PINTernal COMPressibility PEXTernal PCOUpling PREFerenceVOLUme

Noncovalent bond specifi-cations

Hydrogen-bond specification and nonbond specification are supported.

GENERATE

Purpose

The GENERATE subcommand (within a MODES command block) isused to calculate modes for the specified body.

Syntax

MBOND [NBODY integer]MODES [KEYWORD [value] ]

…GENERATE body_name [KEYWORD [value] ]

SUBCOMMAND [value][SUBCOMMAND [value] ]

ENDEND

END

86 MBO(N)D


Notes

All CHARMm’s control and command parsing options are supportedwithin the GENErate block. In particular, this allows for different streamfiles to be created and used to generate modes for each body in a system.

Any previously loaded (or generated) modes for the specified body arecleared.

DELOcalization—The delocalization is a measure of how localized a par-ticular mode is. It is the ratio of the fourth moment of the displacementalong the mode vector and the second-moment squared, i.e.:

commandkeyword

subcommandkeyword value default meaning

GENErate body_name Start a GENERATE sub-block for body_name(character*4 string).

NMODE integer 20 The number of modes to be generated.

ALL May be used for all modes if sufficient memory isavailable.

DELOcalization If keyword is present, compute the delocalization ofeach generated mode and store it as the secondproperty of that mode (the frequency is the first)(see Notes).

SHOW Echo the information as it is calculated.

MINI minimize_spec See CHARMm Dictionary (online).

DIAG Compute the Hessian for atoms in the selected bodyand diagonalize it. Discard the six translational/rotational modes.

FIXED Include the interactions between atoms in this bodyand other atoms in the system when computingthe Hessian.

VACUUM VACUUM Ignore these external interactions.

SORT FREQ FREQ Sort the generated modes by frequency (most nega-tive to most positive).

DELOcalization Sort according to the delocalization factor.

SHOW Echo the information as it is calculated.

WRITE write_spec Save selected modes (see Notes).

END End the GENERATE sub-block.


MBO(N)D 87

Eq. 12

In very localized modes this ratio is close to 1; in very delocalized modesit is close to 0. At very high frequencies, multiple occurrences of localizedmodes (e.g., C–H stretching), have a small delocalization value.

MINImization—All CHARMm minimization options are supported. Allatoms that do not belong to the specified body are fixed for the duration ofthe GENErate command (all atoms are restored to their initial coordinateson exit).

WRITe—Save the range of selected modes to the specified UNIT in theformat that LOAD uses (Notes). They are saved in the current order (i.e.,sorted by frequency or by delocalization).

The syntax of the WRITE subcommand is:

WRITE {[NMODe integer] } UNIT integer{[MODE integer THRU integer]}

The possible SORT keys are FREQuency and DELOcalization (above). Ifthe DELOcalization has not already been computed, it is computed auto-matically.

The syntax of the SORT subcommand is:

SORT {[char*4]} {[FREQ]}{[ALL]} {[DELOcalization]}

MBOND

Purpose

The MBOND command is used for setting up the system and controllingits activation.

r14

i

atoms

�

r12

i

atoms

��

2-------------------------

88 MBO(N)D


Syntax

MBOND [SUBCOMMAND, … [value …] ]

or:

MBOND [NBODY integer][sub_block] ]

ENDEND

Notes

The MBOND command can be used either as a single-line command(mainly for control and status reports) or as an opening for a commandblock (for setting up the system substructuring and mode assignments).

commandkeyword

subcommand key-word value default meaning

MBOND ON ON Activate MBO(N)D and take substructuring into accountwhen calculating energy, etc.

OFF Deactivate MBO(N)D (all data structures are keptintact).

CLEAR Deactivate MBO(N)D and remove all related data struc-tures from memory.

STATus Print out MBO(N)D status report (including number ofbodies, size, mode information, etc.).

SHORt Give global status.

LONG LONG Add body information (see Notes).

VLONg Add mode information (see Notes).

ELECtrostatics Not available.

ATOM Use full, nonlinear forces (see Notes).

MBOND Start a MBO(N)D command block.

NBODY integer Specify the maximum number of bodies to support (seeNotes).

SUBStructure See SUBStructure.

MODES See MODES.

MTS See MTS integrator.

END End the MBO(N)D command block.


MBO(N)D 89

NBODY needs to be specified only once per CHARMm run. To minimizememory usage, it is useful to keep this number small. If you change thevalue of NBODY within a CHARMm run, then all previously definedstructures are erased. NBODY must be a positive number.

Within the MBOND command block, all of CHARMm’s miscellaneouscommands can be used. This allows command-line control: streaming files,goto, labels, if statements, etc.

All the single-line commands can be also used within the MBOND com-mand block (but not within the SUBStructure and MODES sub-blocks).

For the LONG and VLONg options of the STATus subcommand, you canspecify a body_name; the default is all bodies.

ATOM—This is the default, for using the full, nonlinear forces.

MODES

Purpose

The MODES command is a subparser (within an MBOND commandblock, see General format of MBO(N)D command block) that is used togenerate and specify modes, in order to have flexible bodies.

Syntax

MBOND [NBODY integer]MODES [KEYWORD [value] ]

SUBCOMMAND [value][SUBCOMMAND [value] ][GENERATE sub-block]

ENDEND

90 MBO(N)D


Notes

HARM keyword The following commands work only if the HARM keyword is present.

FCON Defines a single force constant of the harmonic potential to beused for mode-generation. When the MULT command is on there is noneed to define FCON.

RCUT Defines the cutoff distance for pairing atoms. Only distance cri-teria are used to define a pair of atoms.

commandkeyword


MODEs Start a MODEs sub-block.

HARMonic Invokes the harmonic potential mode generation for theflexible body. A simple harmonic potential (instead ofthe regular CHARMM potential) is used to generatedmodes for the body.

KEEP KEEP Keep the mode information (eigenvectors, frequencies,nominal coordinates) in CHARMm memory afterpassing it to MBO(N)D.

DELEte Remove the mode information after interfacing withMBO(N)D.

NMODe integer 20 Set a value for the number of modes to be loaded with theLOAD subcommand.

LOAD load_spec Load the mode information for the body from a file (seeNotes).

UNLOad body_name Turn the flexible body with body_name (character*4string) into a rigid body. Not needed when LOADingor GENErating new modes for a flexible body.

ALL Remove all mode information for all bodies.

USEM use_spec ALL Specify which modes to use in the dynamics calculation(see Notes).

PED body_name Analyze body-based modes by printing the expectationvalue of the energy contribution change for each inter-nal coordinate term (see Notes).

GENERATE sub-block See GENERATE.

SORT sort_spec Sort the modes (see Notes).

END End the MODEs sub-block.


MBO(N)D 91

VDWR Sets an initial cutoff distance as a sum of van der Waals radii ofinteracting atoms.

Final cutoff distance = RCUT + VDWRatom1 +VDWRatom2

Optional commands forharmonic potential modes

BOND, ANGLE, ALL These options override the distance criteria fordefining a pair of atoms. The BOND command forces bonded atoms tobe an interaction pair. The ANGLE command forces the pairing ofatoms which have a common atom center. The ALL command invokesboth BOND and ANGLE commands. The remaining atoms are pairedby the distance criteria.

MULTiple Implies the use of different force constants based on thenature of the interactions. Each harmonic force constant is obtainedfrom the CHARMM parameters, such as bond, angle, Lennard-Jones(VDW) parameters, and converted to linear spring constant.

VDWF In the MULT selection, the force constant (K) between thosepaired atoms that are connected by the distance criteria, is defined bythe second derivative of the Lennard-Jones potential (K = d2V/dr2)evaluated at current distance between the atoms. If VDWF is on, it isevaluated at the potential minimum.

Flexibility of multiatombodies

All multiatom bodies (defined in the SUBStructure sub-block) areassumed rigid unless explicitly defined as flexible in the MODES sub-block. To identify a body as flexible, a set of modes can be generated orloaded from a file. In addition, modes can be sorted, by frequency or bydelocalization.

LOAD command The LOAD command reads the body-based nominal coordinates, themodal stiffness matrix, and either the first NMODE eigenvectors or theeigenvectors in the range MODE integer THRU integer. If this body isalready defined as flexible, a call to LOAD overwrites the previous modeinformation. An appropriate unit has to be opened before using the LOADcommand.

The syntax of the LOAD subcommand is:

LOAD body_name {[NMODe integer] } UNIT integer{[MODE integer THRU integer]} [SHOW] [NOVEC]

The body_name can be any character*4 string. UNIT specifies the location(integer) of the formatted file containing the mode information. SHOWcauses the information read from the file to be echoed. NOVEC, if present,means to read the modal-stiffness matrix and properties without reading theeigenvectors.

92 MBO(N)D


Use the first NMODE modes or MODE integer THRU integer in thedynamics calculation. The default is all the loaded modes. The number ofmodes used cannot exceed the number of modes LOADed or GENErated.The USEM command does not free memory, so that the loaded modes canbe accessed again if needed.

The syntax of the USEM subcommand is:

USEM {[body_name]} {[NMODe number_of_modes] }{[ALL]} {[MODE integer THRU integer]}

The number_of_modes is an integer. USEM ALL … means to use thespecified mode numbers for all bodies.

PED is a facility in CHARMm to analyze body based modes. The syntaxof the PED subcommand is:

PED char*4 [mode_spec] [magnitude_spec] [TOL real]

[mode_spec] is a choice of either NMODES N (i.e., the first N modes) orMODE M THRU N.

See CHARMm’s Vibran documentation for a description of [magnitude_spec]. For a given magnitude specification, CHARMm computes theexpectation value for the energy contribution change for each internal coor-dinate term (bond, angle, dihedral, and improper dihedral) and prints thatterm if the fluctuation is greater than the tolerance (default TOL 0.0001).

Modes must have been loaded for the specified body (by either LOAD orGENERATE). Only vacuum modes are supported (i.e., contributions fromatoms outside the body are not included).

Modes can be sorted at times other than during GENEration (GENERATE).For example, if modes are computed using some other program, thenloaded into CHARMm, they can be still be sorted. The possible keywordsare FREQuency and DELOcalization (GENERATE). If the DELOcaliza-tion has not already been computed, it is computed automatically.

SORT subcommand The syntax of the SORT subcommand is:

SORT {[char*4]} {[FREQ]}{[ALL]} {[DELOcalization]}


MBO(N)D 93

MTS integrator

Purpose

The MTS keyword signifies that the subsequent dynamics run is to usemultiple time scales. This keyword sets up the necessary data structures tosupport multiple time scales.

Syntax

MBOND [NBODY integer]MTS

MASS [CALIbration f]DISTance

LINEar ACUTOn R

ENDRATIos K L M …MAXStep tCLEAr

ENDEND

commandkeyword

subcommandkeyword

value oroption default meaning

MTS MASS none none Specifies that reduced mass is used to segregate nonbondforce. This keyword must be present.

CALIbrate real 0.5 Co factor from Eq. 1.

RATIos K,L,M, … none Specifies the interaction binning ratio (1 < K < L …). K,L, … are integers. Up to 4 binnings are supported.

DISTance Invokes distance-dependent factor Cr in binning criterion.Omitting the DIST … END block of commands isequivalent to setting Cr = 1 in Eq. 1.

LINEar real 0.8 A,parameter in Eq. 2.

CUTOn real 5.0 ro in Eq. 2.

MAXStep real 0.1 100 fs time step limit for largest time step.

CLEAr Disable body-based multiple time scale method and clearall MTS parameters.

94 MBO(N)D


Notes A valid substructuring must have been defined before invoking the MTSkeyword.

The MTS keyword signifies that the subsequent dynamics run is to utilizemultiple time steps. This keyword sets up the necessary data structures tosupport multiple time steps. Dynamics is initiated only with the DYNAMBOND command.

The MBOND keyword must be specified before calling MTS. Otherwise,CHARMm MTS dynamics is invoked.

The number of stages, binning ratios, for the multiple time step method canbe explicitly specified by the RATIos keyword. Or the stages can be auto-matically calculated by not specifying the RATIos keyword.

The MASS keyword specifies that the interaction mass, defined in Eq. 1, isused to segregate the nonbond force. The interaction mass depends on thesubstructuring employed: for an atom in an atomistic region, it is the massof that atom; for an atom in a rigid body, it is the combined mass of allatoms in that body; for an atom in a flexible body, it is the mass of the atom.

MASS CALI keyword can calibrate multiple-binning as defined by Eq. 1.That is, the value of MASS CALI scales the interaction mass. Changingthe CALI value from 0.5 to 1.2 could alter the MTS behavior from verycautious to very aggressive.

If you use the DISTANCE keyword (recommended), the interaction massis multiplied by a DISTANCE factor C(r), defined in Eq. 1(where r is thedistance between the two atoms or bodies).

In MBO(N)D-MTSL, only nonbond interactions are treated. Other inter-actions, such as dihedral, angle bending, etc., are computed at the fastesttime step.

If you want to explicitly define both the number of bins and the differentnonbond computation rates, use the RATIos keyword. Up to 4 values maybe provided. The fastest rate is always 1 and the values provided must bemonotonically increasing and greater than one. The number of values pro-vided determines the number of bins—i. e., if one value is provided, thenonbond interactions are separated into two stages; if 3 values are provided,4 stages are used.

Update frequencies in dynamics, such as nonbond update, reporting, etc.,are modified to be the lowest common multiple (LCM) value of the MTSfrequencies.

For example:


MBO(N)D 95

RATIo 2 3 4 6 LCM = 12 ,

On the other hand:

RATIo 2 3 4 5 LCM = 60.

The first command may be a better choice than the second one, since itallows a more frequent update, which may be useful for some runs.

The MAXStep keyword is useful if you are using a large value for thetimestep in the DYNAMICS command and the automatic computationmay be producing huge net timesteps for the slowest update rate.

In theory, the interaction mass of atoms in a flexible body can be larger thanthe mass of the individual atom. But in practice the benefits of doing thisare not very great.

If you already have a large base timestep (15 or 20 fs), it is best to specifythe exact ratios rather than compute them automatically.

Examples 1. Suggested (rather conservative) options.

The RATIO keyword is omitted—this causes automatic generation ofbins.

MTSMASS CALI 0.5DISTANCE

LINEAR 0.8CUTON 5.0

ENDEND

2. More experimental strategy.

You can try, for example, 1.0 - 1.2 for the calibration factor, keeping allother parameters fixed. A larger calibration factor causes more interactionsto be assigned to slower bins, which results in more speed, but might causeinstabilities.

MTSMASS CALI 1.0 ! 0.5 < A < 1.2DISTANCE

LINEAR 0.8CUTON 5.0

ENDEND

96 MBO(N)D


3. Aggressive strategy.

Important! Use this type of setting only after carefully reading the docu-mentation. You need to know what you are doing and be willing to spendsome time experimenting with different settings, to squeeze the most out ofthe integrator, For example:

MTSMASS CALI 1.5DISTANCE

LINEAR 0.8 1.0CUTON 4.0

ENDRATIos 2 3 4 6MAXStep 0.2

END

The trade-off here is to try to move as many as possible pairwise interac-tions to slower bins (and to make the slower bins as slow as possible) with-out loosing too much accuracy and stability of the integrator.

SUBStructure

Purpose

The SUBStructure subcommand (within an MBOND command block,see General format of MBO(N)D command block) is used to identify col-lections of atoms to be grouped into bodies.

Syntax

MBOND [NBODY integer]SUBSTRUCTURE

BODY body_spec[SUBCOMMAND [value] ]…

ENDEND


MBO(N)D 97

Notes

A body is identified using the SELECTION facility of CHARMm (seehypertext CHARMm documentation).

The syntax of the BODY subcommand is:

BODY body_name SELEct (...) END [SHOW]

The body_name can be any character*4 string. SHOW prints out informa-tion about the body just defined.

Generally, bodies are composed of contiguous atoms, although there is norestriction that they be so (e.g., you could define a set of water moleculesas a body). Bodies can have any name of four characters, except “ALL “.

When body identification has been completed, the CODES array and non-bond list are updated to reflect the reduced number of interactions.

The PARTICLE keyword means that the MBO(N)D method is used foratomistic dynamics simulations. This is sometimes useful for direct com-parison with CHARMm atomistic simulations.

commandkeyword


SUBStructure Start a SUBStructure sub-block.

BODY body_spec Specify the body to be defined.

HINGE BOND BOND Constrain all bonds between bodies and within atomisticregions of the model.

ANGLE Not available.

DIHEdral Not available.

OFF Do not constrain bonds.

PARTICLE Define each atom as a separate body.

END End the SUBStructure sub-block.

98 MBO(N)D


MBO(N)D 99

Aaccuracy 29Amadei, A. 20, 75Animate Modes 62Askar, A. 76atoms

degrees of freedom 15single 15temperature 24

BB factors, analysis 34background jobs

completion status 57default host 57default mode 56electronic mail notification 56execution mode 56job number 56monitoring 59network queuing system 57notification window 57preferred host 56saving command file 57

Benfield, W. A. 21, 75Berendsen thermostat 24Berendsen, H. J. C. 75Berne, B. J. 76bodies

component modes 15, 20, 50defining in standalone mode 68dynamics 19flexible 15, 30, 31, 32, 35force vector 20hinges 18inertial frame 19keywords 96modal force vector 20motion 15net force vector 16

particle 15protein secondary structure 30pseudodihedral analysis 31, 44reference frame 18, 22rigid 15, 20, 30, 31, 32, 35saving definitions 49size 30temperature 24torque vector 20vibrations 15

Bodies pulldown 61Bodley, C. S. 10, 75bold type, meaning 81Brooks, B. R. 75Bruccoleri, R. E. 75

Cχ-angle analysis 32Chun, H. M. 20, 75, 76closed topological loops 35Color Bodies 62commands

descriptions 83documentation format 13entering on command line in Insight pro-

gram 13format 81

Completion_Status Background_Job 64component modes 39

animating 50approach 21boundary conditions 21definition 21dynamics 22fixed environment modes 21, 22generation 20, 22, 49generation methods 22generation procedure 22keywords 85, 89loading into Insight 50reference coordinates 36

Index

100 MBO(N)D

D

room temperature 36system eigenvectors 22technique 21vacuum modes 21, 22

computational efficiency 10, 29, 33, 35conformational changes 10conformational differences 34constraints

algorithm 25closed topological loops 35dynamics 25, 53, 54temperature 25

Control_Bkgd_Job Background_Job 64covariance mode analysis 21Craig, R. R., Jr. 21, 75curly braces, meaning 81

DDefine Bodies 61Delete Bodies 62Devers, A. D. 75Ding, H.-Q. 75Durand, P. 21, 75dynamics

accuracy 33analysis 39atomistic 39atomistic data-collection 39, 53atomistic or MBO(N)D 58bodies 19body size 24, 33classical vs. MBO(N)D 9component modes 21, 22constraints 25degrees of freedom 15efficiency in MBO(N)D 16energy results 39equilibration 39, 53essential 29, 33final setup 58initialization 37, 68integrator 58, 69, 93keywords 83MBO(N)D data-collection 39minimization before 38multibody 22, 39multigranularity 33

output 39, 54precautions 24procedure 37, 68setting up in Insight 51, 52setting up in standalone mode 68substructured 29temperature 24, 39timesteps 33, 53, 54

Dynamics SetUp 63

EEdit Bodies 62ellipses, meaning 81energy, constant 54

Ffiles

background_job_hosts 56bodies 49CHARMm 67, 77charmm.cfrc 42charmm19.cfrc 42charmm22.cfrc 42.com 67command input 58, 69component modes 49, 67.crd 37dynamics 39energy 39.inp 67input 67, 77input script 69input structure 37MBO(N)D-specific 77.psf 37reading 69restart 39.rst 37.str 49substructuring 67trajectory 39velocity 39

Files SetUp 63forcefields

applying to model 42filenames 42

G

MBO(N)D 101

Harvard 42location 42MSI CHARMm 42specifying 42

free energy changes 10Frisch, H. P. 75

GGallion, S. 76Generate Modes 62Get Bodies 61Go, N. 20, 75, 76Goddard, W. A., III 75Greengard, L. 75Gunsteren, W. F. 76

HHao, M.-H. 21, 75Harvey, S. C. 21, 75help, on-line 13, 41Horiuchi, T. 20, 75Hruda, R. F. 75

IIchiye, T. 20, 75Insight program 11interpeptide plane angle

analysis 31beta sheets 31

italic type, meaning 81

KKarasawa, N. 75Karplus, M. 20, 75Kidera, A. 76Kill_Bkgd_Job Background_Job 64Kushick, J. 75

LLee, A. Y. 21, 75Levy, R. M. 20, 75

Linssen, A. B. M. 75List Bodies 62Load Modes 62Lobatto integrator 26

time-reversible multiple-time-scale variant27

Lupi, V. 76

MMartyna, G. J. 76MBO(N)D

and CHARMm 27approach 10, 15body-based simulation technique 10commands 69component mode generation methods 22constraints 25executables 79in Insight environment 10initialization 37maximizing performance 33multigranularity 33preliminary tasks 41PSF or RTF mode 55restarting 58standalone mode 11, 67, 79starting 11, 61, 67starting structure 37strategy 29tutorial 73

MBOND module 11, 41, 61accessing 42

mbond.exe 11, 67MBond_Run MBond_Run 63MBond_Run pulldown 63Minimize SetUp 63Mizuguchi, K. 20, 76models

alpha helices 30atoms, rigid bodies, and flexible bodies 16beta bridges 31beta sheets 30, 31domains 30linker regions 30loop and turn regions 32minimization in Insight 43multibody description 17

102 MBO(N)D

N

sidechains 30, 32substructure vs. atomistic 10substructured 17, 29

Modes pulldown 62Molecular Simulations, Inc.

documentation library 13website 13

Momany, F. 42Momany, F. A. 76MTS_Integrator SetUp 63

Nnonbond interactions 51Nonbond SetUp 63normal mode analysis 21, 36

OOlafson, B. D. 75Optimize MBond_Run 63

PParameter_Mode SetUp 63Park, A. C. 75Perahia, D. 75pseudodihedral analysis

alpha helical regions 31, 44pseudodihedral angles

analysis 30definition 30

Put Bodies 61

RRabitz, H. 76Rokhlin, V. 75Rone, R. 42, 76

SSanejouand, Y.-H. 75Scheraga, H. A. 21, 75secondary structure

calculated 35

dynamic 35SetUp pulldown 63Setup_Bkgd_Job Background_Job 63Singh, U. C. 76Space, B. 20, 76square brackets, meaning 81standalone mode of MBO(N)D 11States, D. J. 75static modes 21substructuring 15

files 67keywords 96motion expected 20optimal 29strategy 20, 29, 32, 33, 34within Insight 43

Swaminathan, S. 75system modes

definition 21eigensolution 21generating 20

Ttemperature

atomistic 24bodies 24changes 24constant 24, 53constraints 25control 24initial 24

temperature factors 34thermal motion about equilibrium structure

34time scales

body size 16in MBO(N)D 16Lobatto integrator 27multiple 16, 33, 68separation 16

Trinquier, G. 75Tsuha, W. S. 21, 75Tuckerman, M. 76Turner, J. D. 10, 75, 76

W

MBO(N)D 103

WWeiner, P. K. 76Wilkinson, A. J. 76

Documents

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