Visualizing Functional Motions of Membrane Transporters at an Atomic Resolution

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Large‐scale conformational changes are central to the function of membrane transporters. Description of these structural changes, however, requires sampling high‐dimensional free energy landscapes that are inaccessible to experimental techniques and conventional computational methods. Combining advanced molecular simulation techniques and free energy methods, guided by experimental data, we have recently developed a novel computational approach that, while expensive, has been the most efficient way to describe large‐scale structural transitions in membrane transporters [PNAS 110:18916‐21 (2013); JCTC 10: 2866–80 (2014)]. The approach is based on simulations of large macromolecular systems preserving realistic representations of the systems in explicit membranes. Here we describe the application of the methodology to the study of several classes of membrane transporters, in order to characterize the inter‐conversion of these molecular devices between the major conformational states necessary for their function, to characterize the free energy profiles associated with these transitions, and more importantly how chemical details such as ion/substrate binding drastically modulate the energy landscapes. The results of these simulations elucidate highly relevant mechanistic details of the function of membrane transporters providing a detailed structural basis for the experimentally observed phenomena.