A Hamiltonian Replica Exchange Molecular Dynamics (MD) Method for the Study of Folding, Based on the Analysis of the Stabilization Determinants of Proteins

Massimiliano Meli,Giorgio Colombo

doi:10.3390/ijms140612157

Abstract

Herein, we present a novel Hamiltonian replica exchange protocol for classical molecular dynamics simulations of protein folding/unfolding. The scheme starts from the analysis of the energy-networks responsible for the stabilization of the folded conformation, by means of the energy-decomposition approach. In this framework, the compact energetic map of the native state is generated by a preliminary short molecular dynamics (MD) simulation of the protein in explicit solvent. This map is simplified by means of an eigenvalue decomposition. The highest components of the eigenvector associated with the lowest eigenvalue indicate which sites, named “hot spots”, are likely to be responsible for the stability and correct folding of the protein. In the Hamiltonian replica exchange protocol, we use modified force-field parameters to treat the interparticle non-bonded potentials of the hot spots within the protein and between protein and solvent atoms, leaving unperturbed those relative to all other residues, as well as solvent-solvent interactions. We show that it is possible to reversibly simulate the folding/unfolding behavior of two test proteins, namely Villin HeadPiece HP35 (35 residues) and Protein A (62 residues), using a limited number of replicas. We next discuss possible implications for the study of folding mechanisms via all atom simulations.

Highlights

The investigation of the mechanisms underpinning protein structure formation and stability represents a central interest for structural biology
The aim of H-replica exchange MD (REMD) approaches is to enhance conformational space sampling compared to classical molecular dynamics (MD)
The use of Hamiltonians with modified non-bonded interaction parameters introduced by Affentranger and coworkers is interesting, as it enhances conformational space sampling by affecting the interactions that most directly determine the dynamic properties of the system [16,17]

Summary

Introduction

The investigation of the mechanisms underpinning protein structure formation and stability represents a central interest for structural biology. An additional problem is represented by the presence of multiple energy minima, separated by free-energy barriers, whose heights are often larger than the thermal energy available to the system, causing trajectories to be trapped and confined to local minima To overcome these limitations, several approaches to increase conformational sampling have been developed over the years: simulated annealing [1], potential scaling [2,3,4], locally enhanced sampling [5], parallel tempering [6], hyperdynamics [7], metadynamics [8] and the adaptive biasing force method have all been proposed to overcome sampling limitations during molecular simulations

Methods

Results

Conclusion