Membrane transporters are specialized molecular devices that use various forms of cellular energy to drive active transport of specific substrates across the membrane. Their fundamental role in diverse key biological processes has placed them among central drug targets, furthering widespread interest in their biophysical and mechanistic studies at a molecular level. 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 conventional sampling techniques such as regular molecular dynamics (MD) simulations. We have recently developed a novel computational approach that, while being numerically expensive, has been the most efficient way to describe large-scale structural transitions in membrane transporters (as well as for any other macromolecular systems) using non-equilibrium methods employing system-specific collective variables, and a novel combination of several state-of-the-art sampling techniques [PNAS 110:18916-21 (2013); JCTC 10: 2866–80 (2014)]. The approach is based on loosely coupled, multiple-copy MD 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.

Visualizing complex functional motions of membrane transporters using advanced simulation and free energy techniques

249th National Meeting (2015)

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