Physics Based Structure Refinement in Casp11 using Geometric Unfolding and Hierarchically Restrained Replica Exchange Molecular Dynamics

Abstract

We have developed a new physics based approach to the protein refinement problem by mimicking the mechanism of chaperons that rehabilitate proteins. The template structure is unfolded by selectively pulling on different portions of the protein using the geometric based technique FRODA, and refolding the protein using hierarchically restrained replica exchange molecular dynamics. FRODA unfolding is used to create a diverse set of topologies for surveying near the native like structures from a template. The unfolding trajectories are then used to find energetic restraints to enforce contacts and dihedral restraints. An REMD simulation is performed for the entire ensemble using consensus and reservoir techniques, which allow multiple structural candidates to “swap” into the replica cascade at the highest temperature replica and the most favorable folds to propagate to the lowest temperature replica. The restraints are added in a hierarchical fashion where local contacts are restrained first followed by the addition of non-local restraints to narrow the conformational search toward the native state. After REMD structures are clustered, refined structures are selected based on the highest populated cluster, RMSD and DFIRE score.