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School of Science Institute for
Mathematical Modeling and
Computational Science

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Computational Modeling of Membrane Transporters

PI: F. Zhu (Department of Physics, IUPUI) 

Cell membrane creates a barrier that separates the inside of the cell from the outside, thereby preventing the passage of most hydrophilic molecules. Membrane transporters are designed to transfer materials across this barrier. They perform a wide range of biological functions, from the uptake of nutrients in bacteria to the generation of membrane potential in human cells. By coupling to energy sources such as ATP hydrolysis, some transporters can actively pump the substrates across the membrane against the concentration gradient. Conformational change is the key step in the functioning of membrane transporters. According to the “alternating access model”, membrane transporters adopt an outward- or an inward-facing conformation, and the alternating transitions between these two conformations drive the translocation of the substrate. Although in recent years a growing number of transporter structures have become available, the key question – how the proteins change their shape from one state to the other – remains largely elusive. Through computational modeling and simulations, the proposed study aims to quantitatively characterize the transition between the two conformations. We will apply advanced sampling techniques to identify the transition pathway at atomic resolution, and to reveal the thermodynamics and kinetics of the transition, making it possible to predict experimental observables such as the net substrate transport rate. The outcome of this project will thus provide important insight into the mechanism of these molecular machines.