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 membrane proteins that use pre-existing molecular concentration gradients as an energy source for translocating another substrate, such as a nutrient or a neurotransmitter, against its concentration gradient. This process requires the protein to change conformations so as to expose a pathway to the substrate binding site(s) on one or other side of the membrane, in a cycle known as alternating access. Every organism expresses dozens of different secondary transporter proteins, and these exhibit a diverse set of architectures, albeit always with some form of internal structural symmetry. Unprecedented, ground-breaking insights have been garnered from three-dimensional structures obtained in the last decade. Nevertheless, a detailed understanding of the mechanism of each membrane transport protein, and how it is regulated by factors in its environment, requires knowledge of its structure in many more conformational states, including identification of the binding regions for the substrate or substrates. In addition, highly-dynamic segments at either end of the protein, which are often responsible for regulatory roles, require additional effort to characterize. Ongoing studies from our group over the last year have continued to investigate these questions for 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.