Interactions in Non-Native States of Proteins

Scripps Research Institute, La Jolla CA

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): This proposal requests support for an ongoing collaboration among three faculty members, aimed at the development of molecular simulation protocols to study the conformations and energetics of both native and non-native states of peptides and proteins, and to explore the details of pH- and salt-induced conformational transitions. The primary computational tools will be continuum solvent models for conformational energetics and molecular dynamics in "extended" ensembles for conformational sampling. Critical tests of the continuum solvent models will concentrate on potentials of mean force for folding/unfolding transitions in helical and beta-hairpin peptides. Based on these studies, a "second generation" of generalized Born solvation models will be developed, which will be incorporated into the CHARMM and Amber molecular dynamics packages. This, in turn, should allow continuum solvent models to become efficient enough to allow us to carry out constant pH simulations, in which the protonation state of amino acid sides chains is brought to equilibrium with an external bath of protons at a given pH (via a Monte Carlo procedure) at the same time that the conformational states of the system are sampled via molecular dynamics. We will accelerate sampling through "replica exchange" methods, where parallel simulations at various pH values are run, and periodically swap configurations among themselves. This combination of continuum solvent ideas and more sophisticated sampling techniques should allow us to develop practical simulation tools in which the user specifies pH and salt concentration as external thermodynamic variables, in much the same way that temperature and pressure are specified currently. This will facilitate MD simulations under these more relevant biochemical conditions to be easily accessible to a wider community.