This allocation supports work to develop an understanding of biological processes by which molecular machines transport substrates and signals across membranes. The project is a key element in a research program that aims to determine the functional properties and modes of action of membrane proteins in the family of secondary transporters as prototypical biological machines of the cell. Our goal is to understand their functions under normal conditions, and under conditions impacted by interactions with their environments, including changes in membrane components and various forms of energy coupling, e.g., through various chemical gradients. Here we study computationally a specific member of the family of sodium-coupled symporters (Na+-powered substrate transporters across cell membranes) and the key components of its transport-assembly (i.e., the membrane and protein complex essential for transporter functions). The mechanistic study of this protein, the dopamine transporter DAT, at the unprecedented level of computational molecular dynamics presents the distinct advantage of addressing a system that is being intensively investigated experimentally due to its very high significance in biology, in human physiology, and in medicine. As a result the specific protein members of its functional environment are also well characterized and broadly investigated. Using advanced methods of computational simulation and multiscale analysis, the aim is to uncover detailed dynamic properties and energetics of these complex molecular machines under the various relevant conditions. Through extensive multi-scale, integrative computational approaches, carried out on unprecedented spatial/temporal scales, we seek to uncover thermodynamics-based insights into chemical environment and factors necessary to maintain tight control of two key physiological energy transduction processes: transporter-mediated reuptake and substrate efflux. The outcome of this proposal will be an improved understanding of the molecular mechanisms of energy-driven transport and signaling across membranes which are essential for the construction of predictive computational models of complex biological processes and their use in various bioengineering projects.
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