Chapter 7: Computational Characterization of Molecular Mechanisms of Membrane Transporter Function

Transport of materials across the cellular membrane is a fundamental process in biology. Active membrane transporters constitute one of the major classes of proteins that mediate this process, and they do so in a highly regulated and selective manner. In order to transport substrates uphill, these molecular machines rely on a diverse spectrum of conformational changes spanning multiple time and size scales, and they couple these motions to various sources of energy, including transmembrane electrochemical gradients and ATP hydrolysis. Computational techniques such as molecular dynamics simulations and free energy calculations provide us with a powerful repertoire of biophysical tools offering unparalleled spatial and temporal resolutions that complement experimental methodologies and help us understand the molecular basis of function in membrane transporters. In this chapter, we present an overview of a number of examples of recent studies performed in our own lab in which computational methods and simulation techniques have been successfully employed to investigate and to characterize the microscopic molecular events that underlie membrane transporter function. While highlighting a number of recent approaches developed specifically to tackle challenging problems in membrane transporters, e.g., characterizing the nature of large-scale conformational changes, the presented studies also provide examples of a variety of mechanistically interesting and biologically important transporter systems.