title: A Hamiltonian replica exchange molecular dynamics (MD) method for the study of folding, based on the analysis of the stabilization determinants of proteins.
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.
authors.affiliation: Istituto di Chimica del Riconoscimento Molecolare, CNR, Via Mario Bianco 9, Milano 20131, Italy. g.colombo@icrm.cnr.it.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Meli
authors.forename: Giorgio
authors.initials: G
authors.lastname: Colombo
mesh_terms: D008840:Microfilament Proteins / Q000737:chemistry* / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D017510:Protein Folding; D055550:Protein Stability; D017433:Protein Structure, Secondary; D013205:Staphylococcal Protein A / Q000737:chemistry* / Q000378:metabolism*; D013816:Thermodynamics; D013997:Time Factors
chemical_list: D008840:Microfilament Proteins; D013205:Staphylococcal Protein A; C026615:villin