Protein Structure Refinement via Molecular Dynamics Simulations

Abstract

Computational protein structure prediction has long been an important alternative to experimental structure determination. Comparative modeling approaches can often generate approximate models but generating highly accurate models that are comparable to experimental structures has remained a significant challenge. Refinement methods via molecular dynamics simulations are an avenue for bridging this gap. MD-based protocols that provide consistent but still modest improvement of initial models are presented based on results from recent rounds of CASP. Furthermore, new detailed analysis of microsecond simulations combined with Markov state modeling was used to construct energy landscapes that connect initial homology models to native structures. These maps provide insight into the key kinetic barriers and energetics along transition pathways from homology models towards the native state and inform the design of more effective structure refinement protocols that can truly reach the native state from initial comparative models.