Enhanced Sampling of Protein Conformational Transitions via Dynamically Optimized Collective Variables

Protein conformational transitions often involve many slow degrees of freedom. Their knowledge would give distinctive advantages because it provides chemical and mechanistic insight and accelerates the convergence of enhanced sampling techniques that rely on collective variables. In this study, we implemented a recently developed variational approach to conformational dynamics metadynamics to the conformational transition of the moderate size protein, L99A T4 Lysozyme. To find the slow modes of the system, we combined data coming from NMR experiments as well as from short MD simulations. A Metadynamics simulation based on these information reveals the presence of two intermediate states, at an affordable computational cost.