Simulation methods rooted in molecular-mechanics-based approaches are ideally suited to probe many types of biophysical processes, but it has proven difficult to maintain the desired resolution in simulations and simultaneously achieve the required timescales for observing states of interest at a reasonable computational expense. Given that the knowledge of key conformational states in biomolecules is crucial to rationally design new materials and therapeutic strategies, molecular-scale investigations of these systems necessitate resolving free-energy differences between all states of interest. Given many degrees of freedom in flexible molecules, it is often desired to reconstruct free-energy hypersurfaces in a finite set of variables to obtain information on transition pathways and reactive fluxes. Presented in this talk will be methodological underpinnings of simulation methods that allow reconstruction of such multidimensional free-energy hypersurfaces and searches within them to discover optimal pathways and flux distribution. Applications of these methods to model systems as well as on complex biomolecular systems (e.g. enzymes) and processes (e.g. ligand binding) will be presented.<br/>

Approaches to probe pathways, thermodynamics, and reactive flux in biomolecular systems

2019 Spring National Meeting

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