UTILIZING FORCE FIELD METHODS

TO EXPLORE THE

POTENTIAL ENERGY LANDSCAPES

OF

FLEXIBLE BIOMOLECULESTF10: Zachary S. Davis†, Joanne M. Carr*, Ivan Y. W. Tan*, David J.

Wales*, Timothy S. Zwier†

†Department of Chemistry, Purdue University, West Lafayette, Indiana 47907

*Cambridge University Center for Computational Chemistry, Lensfield Road, Cambridge, United Kingdom CB2 1EW

2

EXPANDING MOLECULAR HORIZONS

There are several challenges we face as we press towards larger and larger molecules:

• Leave behind the realm of relying on chemical intuition

• Increased complexity of potential energy surfaces to explore

• Ab initio lagging behind experiment

Need new methods

Valinomycin

Lignin

3

ADVENT OF NEW TECHNIQUES

Constantly striving for methods that will allow for in-depth study of larger molecules

• Population Transfer Methods• Laser desorption methods• Electrospray ionization• Effective Fragment Potential

Necessary to study the potential energy landscape to gain appreciation of the complexity of larger systems

4

USEFULNESS OF CALCULATIONS

Calculated conformations provide theoretical vibrational frequencies that can be used to assign experimental conformers

5

MULTIPLE EXPERIMENTAL CONFORMERS

When more than one conformer is present in the jet, one or both of the following conditions arise:

1. Two or more conformers have comparable energies

2. If not, large barrier preventing population from cooling into global minimum.

6

MULTIPLE EXPERIMENTAL CONFORMERS

As an ensemble of molecules cools in a supersonic expansion, what pathways are taken?

If we see multiple conformers, what is the barrier to isomerization?

A

B

?

?

7

MULTIPLE EXPERIMENTAL CONFORMERS

To help elucidate the isomerization process, one experimental approach is population transfer spectroscopy

Stimulated Emission Pumping-Population Transfer Spectroscopy

S0

S1

Zero-point Level

CA

B

5. U

V Pr

obe

4. Collisional Cooling

3. U

V D

ump

2. U

V Pu

mp

Excited VibrationalLevel

B*

1. Initial Cooling

6. Fluorescence detection

8

UTILITY OF DISCONNECTIVITY GRAPHS

In either condition, it would be beneficial to be able to examine the potential energy landscape

– Identify transition states and associated barriers– Identify conformational families– Identify excluded minima

D. J. Wales, Int. Rev. Phys. Chem., 2006, 25, 237–282; O. M. Becker, M. Karplus, J. Chem. Phys. 106, 1495-1517 (1997)

‘palm tree’ ‘weeping willow’ ‘banyan tree’

9

UTILITY OF FORCE FIELDS

Benefits• Easily used on large

molecules, clusters, solvated species

• Calculations are done quickly compared to ab initio methods

• Relatively easy to change parameters

Drawbacks• All atoms of the same type

have the same parameters– Bond angles, dihedrals,

force constants, etc.– Different molecular

environments difficult to fully duplicate

• Dispersive interactions are not included

• Energy ordering almost always differs from ab initio

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NUDGED ELASTIC BAND METHOD

A

B

11

NUDGED ELASTIC BAND METHOD

A

B

12

NUDGED ELASTIC BAND METHOD

A

B

13

NUDGED ELASTIC BAND METHOD

A

B

14

SYNTHETIC FOLDAMERS

• Series of capped β-peptides– Ac-(Phe/Ala-Phe/Ala-Phe-Ala)-NHMe

• Number of degrees of freedom increases with number of amino acid residues

• Increasingly complex potential energy landscape and therefore disconnectivity diagrams

15

Β-PEPTIDES C8 (red), AC6 (green), B & C

16

Β-PEPTIDESC8, 21 (red)C8, 23 (green)

17

Β-PEPTIDES

18

CARBOXYBENZYL DERIVATIVES

• By introducing an aromatic N-terminal cap, non-aromatic peptides may be studied

• Polyglycines have been shown to adopt helices in the gas phase

O

O

Carboxybenzyl N-terminal Cap

19

Z-(GLY)3-OH

C10/C7 Structure

20

Z-(GLY)3-OH

C10/C7 Structure

21

Z-(GLY)3-OH

2-7 Ribbon Structure

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

CBZ-(GLY)3-OH

C13; cis in third amide group

38

CBZ-(GLY)5-NHME

39

IN CONCLUSION

• Shift towards larger molecules requires a more in-depth investigation of their associated potential energy landscapes

• Force fields will require reinvestigation as we use them in new ways

• Methods offer test of available force fields• Medium size regime ideal: experiment, ab

initio and force fields all available

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Zwier Group Members:

Dr. Vanesa Vaquero (WG09)

Dr. Ryoji Kusaka (TD09)

Evan Buchanan (WG08, WF12)

James Redwine

Jacob Dean (TF09, WG10)

Deepali Mehta (TG10)

Nathan Kidwell (TG09, FB07)

Joe Korn

Di Zhang (FB08)

Nicole Burke

Joe Gord (MF08)

Patrick Walsh

Special Thanks:

Dr. Chris Whittleston, Cambridge

ACKNOWLEDGEMENTS

CHE-0909619