Computational studies of membrane transport proteins

National Institute Of Neurological Disorders And Stroke

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Abstract

Secondary active transporters are a class of proteins found in cell membranes. They use existing differences in the concentration of molecules as a source of energy to move other substances, like nutrients or neurotransmitters, against their natural flow. This process requires the protein to change to expose a pathway that allows the substance to bind on one or other side of the membrane, in a repeating cycle called alternating access. Every organism contains dozens of different types of these transporter proteins. They have various designs, but they all have a kind of internal pattern of symmetry. Recent discoveries have come from looking at their 3D shapes, which have only been accessible in recent years. Nevertheless, to truly understand how each transporter works and how it is affected by its surroundings, we need to know more about the different shapes it can morph into and where it binds the substances it moves. Moreover, regions at the start and end of these protein that play important roles in cellular control of their transport behaviors are highly flexible and therefore require additional effort to characterize. Ongoing studies from our group have continued to investigate these questions in several different membrane proteins, including serotonin transporter SERT, the betaine symporter BetP, and mitochondrial pyruvate carrier MPC, using advanced structure prediction techniques and molecular dynamics simulations. These efforts are being carried out in collaboration with experimental laboratories, to drive understanding of the mechanism of membrane transport and regulation.