Refinement Of Protein Model Structures In Explicit Solvent Using Biasing Potential Replica Exchange Simulations

Abstract

Comparative protein modeling of a target protein based on sequence similarity to a protein with known structure is widely used to provide structural models of proteins. Frequently, the quality of the target- template sequence alignment is non-uniform along the sequence: parts can be modeled with a high confidence, whereas other parts differ strongly from the template. In principle, molecular dynamics (MD) simulations can be used to refine protein model structures but it is limited by the currently accessible simulation time scales. We have used a recently developed biasing potential replica exchange (BP-Rex) MD method (Kannan, S. Zacharias, M. Proteins 2007, 66, 697-70) to refine homology modeled protein structure at atomic resolution including explicit solvent. In standard Rex-MD simulations several replicas of a system are run in parallel at different temperatures allowing exchanges at preset time intervals. In a BP-RexMD simulation replicas are controlled by various levels of a biasing potential to reduce the energy barriers associated with peptide backbone dihedral transitions. The method requires much fewer replicas for efficient sampling compared with standard temperature RexMD. It is also possible to focus the method to parts of a protein structure (segments of a model structure that may differ strongly from a template structure). Application to several protein structures indicates improved conformational sampling compared to conventional MD simulations. BP-RexMD simulations on several test cases starting from decoy structures deviating significantly from the native structure resulted in final structures in much closer agreement with experiment compared to conventional MD simulations.