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Int. J. Mol. Sci. 2013, 14(6), 12157-12169; doi:10.3390/ijms140612157
Article

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

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Received: 2 April 2013 / Revised: 29 April 2013 / Accepted: 14 May 2013 / Published: 6 June 2013
(This article belongs to the Special Issue Protein Folding 2015)
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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.
Keywords: protein folding; molecular dynamics; protein stability; replica exchange protein folding; molecular dynamics; protein stability; replica exchange
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Meli, M.; Colombo, G. A Hamiltonian Replica Exchange Molecular Dynamics (MD) Method for the Study of Folding, Based on the Analysis of the Stabilization Determinants of Proteins. Int. J. Mol. Sci. 2013, 14, 12157-12169.

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