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Simulation of Conformational Transitions and Free Energy Calculations of PcrA DNA Helicase Hao Wang Molecular Recognition Group School of Pharmacy University of Nottingham

Introduction

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Simulation of Conformational Transitions and Free Energy Calculations of PcrA DNA Helicase Hao Wang Molecular Recognition Group School of Pharmacy University of Nottingham. Introduction. DNA helicases are important enzymes involved in DNA replication, repair, and recombination. - PowerPoint PPT Presentation

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Page 1: Introduction

Simulation of Conformational Transitions and Free Energy

Calculations of PcrA DNA Helicase

Hao WangMolecular Recognition Group

School of PharmacyUniversity of Nottingham

Page 2: Introduction

Introduction DNA helicases are important

enzymes involved in DNA replication, repair, and recombination.

DNA helicases are molecular motors to separate the ds-DNA through the conformational changes coursed by the ATP hydrolysis.

PcrA DNA helicase from Bacillus Stearothermophilus was crystallized by Dale Wigley and Panos Soultanas

Page 3: Introduction

Cell, Vol. 97, 75-84, April 2, 1999

Substrate Complex Product Complex Substrate Complex

Page 4: Introduction

Find the Reaction Pathway of the process from the substrate complex to the product complex.

Calculate the free energy profile along the pathway.

Research Aim

?

Substrate complex Product complex

Page 5: Introduction

Simulation System

637 residues in the protein

15 bases on the short chain of DNA, and 20 bases on the long chain

11439 atoms in protein and DNA

The ATP hydrolysis wasn’t included

Explicit solvent (TIP3P)

52 Na+ ions were added

25419 water molecules were added

87619 atoms in the system

Amber force field

300K

8 CPU years simulation on this project

Page 6: Introduction

The computational methods to simulate the conformational changes of known ended system:

1. Optimize the first guessed pathway between two conformations.

2. Use extra constraints to drive the molecule in the direction of the target structure.

Page 7: Introduction

Start

End

Page 8: Introduction

Chain Minimization Path

Page 9: Introduction

Start

End

Page 10: Introduction

Targeted Molecular Dynamics

Page 11: Introduction

WHAMWeighted Histogram Analysis Method ( WHAM ) is a method using umbrella sampling to provide a free energy profile along a given reaction coordinate.

Umbrella sampling is a well-established free energy technique using an artificial biasing window potential to sample unfavourable areas of conformational space.

Usually this biasing is a standard harmonic potential applied to a bond length, angle or dihedral.

In this research, the RMSD is used as the biasing.

Using the TMD to search a certain RMSD region along the reaction path.

Using WHAM program written by Alan Grossfield.

Computer Physics Communications 91 (1995) 275-282

Page 12: Introduction

Start

End

Page 13: Introduction

RMSD to the product complex along the Chain Minimization path

R

MS

D t

o t

he

pro

du

ct c

om

ple

x a

lon

g t

he

TM

D p

ath

If the two reaction pathway are similar, the RMSD values along the diagonal line should be very small. This picture shows the two methods find a similar path.

Start

End

Page 14: Introduction

Free Energy Profile

Chain Minimisation Targeted MD

The RMSD to the product complex reduces from 3 to 1.7

The free energy of the product complex is higher than that of the substrate complex

The height of free energy barriers are different

The scale of the free energy profiles are different

The ATP hydrolysis only can offer 7.3kcal/mol energy

Page 15: Introduction
Page 16: Introduction
Page 17: Introduction

Future Work

Calculating the Free Energy changes from the product complex to the substrate complex.

Investigating the barriers involved.

Coupling between the ATP hydrolysis and the dynamics.

?

Substrate Complex Product Complex Substrate Complex

√

Page 18: Introduction

Acknowledgments

Dr Charlie Laughton and Dr Stephen Doughty

Dr Panos Soultanas Professor Mark Searle

Everyone in the Molecular Recognition Group

Dr. Ian Withers Ms. Verity Hudson

Mr. Daniel Warner Ms. Michele Burke

Dr. Mark Beardsell Mr. Angelo Pugliese

Mr. Supat Jiranusornkul

University of Nottingham and Spirogen Ltd for funding


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