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

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.