Large-Scale Conformational Transitions in Membrane Transporters Using Advanced Molecular Dynamics Simulations

Explore advanced molecular dynamics simulation techniques in this comprehensive research seminar from the Broad Institute's Models, Inference and Algorithms series. Delve into the computational biophysics approaches for studying large-scale conformational transitions in membrane transporters, essential cellular gatekeepers responsible for moving molecules across cell membranes. Learn about the alternating-access mechanism governing transporter function through inward-facing and outward-facing states, and understand how various simulation techniques are combined to characterize these transitions. Master the process of defining collective variables, conducting driven MD simulations, implementing the string method with swarms of trajectories, and performing bias-exchange umbrella sampling to generate detailed free energy profiles. Examine practical applications of these methods to specific transporters like NaCT, Glt Ph, and GlpT, gaining insights into how structural dynamics influence cellular transport mechanisms and potential drug development strategies. The presentation includes both a primer on computational methodology and detailed case studies demonstrating real-world applications in understanding transporter function and dysfunction in disease contexts.