Physics Based Protein Structure Refinement

Abstract

Accurate protein structure predictions are important for a number of purposes ranging from computational drug design, understanding experimental data and designing new experiments, to the emerging technique of de novo phasing in crystallography. The process of protein structure refinement occurs at the end of the structure prediction pipeline. The goal is to take an approximately correct starting model and further refine the details to produce a more accurate prediction. We have developed a physics-based approach to refinement that combines Hamiltonian exchange molecular dynamics with bioinformatics-derived restraints. The use of restraints dramatically reduces the volume of phase space that must be sampled and makes the procedure practical on small to medium size proteins. We combine this approach with GPU-accelerated molecular dynamics, new implicit solvent models, and recent improvements in force fields. The initial results of this protocol are encouraging and we are able to successfully refine several difficult CASP9 refinement targets.View Large Image | View Hi-Res Image | Download PowerPoint Slide