A Microscopic View of the Mechanisms of Active Transport Across the Cellular Membrane

Abstract Membrane transporters are molecular machines that couple active transport of their specific substrates to various sources of cellular energy through a set of highly coordinated protein conformational changes. The alternating-access mechanism of transport in these proteins, which ensures that the substrate is only accessible from one side of the membrane at any given time, relies on complex and global protein conformational changes that are also closely coupled to molecular events such as substrate binding and translocation. In this review, we describe the application of advanced molecular modeling and simulation technologies to a number of membrane transport proteins studied in our laboratory. The goal is to demonstrate the power of the methods in describing functionally relevant molecular events ranging from more localized events such as substrate binding and gating motions to large, global protein conformational changes governing the transition of the protein between major functional states.