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Center for Nonlinear Studies |
Transport of ions and small molecules across the cell membrane against electrochemical gradients is catalyzed by integral membrane proteins that use a source of free energy to drive the energetically uphill flux of the transported substrate. Secondary active transporters couple the spontaneous influx of a "driving" ion such as Na+ or H+ to the flux of the substrate. The fact that these transporters change their conformation between an inward-facing and outward-facing conformation in a cyclical fashion, called the alternating access mechanism, has been recognized as the general principle underlying secondary transporter function. We have been using molecular dynamics simulations (long equilibrium MD, free energy calculations, enhanced sampling for rare events, constant pH simulations) in combination with experimental techniques such as X-ray crystallography, cryo-electron microscopy, and functional measurements to better understand the mechanism of secondary active transport in a wide range of transporters such as sodium/proton antiporters, bile acid/sodium symporters, the major facilitator superfamily, nucleobase-sodium symporters, and zinc transporters. Identification of the binding sites of ions and substrates together with the moving elements of the alternating access transition shows how a common principle has been implemented by nature in a wide range of protein architectures.
Host: Christoph Junghans