Generalized Work Functional Approach to Identify Reaction Coordinates of Protein Functional Dynamics

Proteins play vital roles in many essential biological processes, ranging from providing structural support and catalyzing enzymatic catalysis to cellular communication and immune defense. The primary goal of protein biophysics is to understand how proteins function. A protein often has multiple functional structures; the conformational changes responsible for transitions between different structures control protein functions. Thus, understanding protein functional dynamics is paramount for elucidating the mechanisms of protein function. A protein conformational change is an activated process: protein must overcome a significant energy barrier that separates the reactant basin (initial structure) from the product basin (finial structure). At the core of this activated process lies the concept of reaction coordinates: the set of essential coordinates that fully determine the progress of a reaction. We developed a generalized work functional approach, a rigorous physics-based method, which enables us to compute reaction coordinates from molecular dynamics trajectories. The exact reaction coordinates identified provide optimal solutions to two major challenges in biomolecular simulations: 1) dimensionality reduction on large-scale simulation data, 2) time scale gap between molecular dynamics simulation and protein functional dynamics. Therefore, our method has great potential in applications to important biological problems, such as ligand binding, allostery, drug design, and free energy calculations.