Thermodynamic Characterization of Conformational Landscape in Proton-Coupled Oligopeptide Transporters

Mahmoud Moradi, University of Arkansas

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Mahmoud Moradi, Kalyan Immadisetty, Mitchell Benton, Seyed Hamid Tabari, Vivek Govind Kumar, Dylan Ogden, Adithya Polasa, Curtis Goolsby, Elonay Yehualashet, UGOCHI ISU, Tariq Salem, Ashkan Fakharzadeh Ghaan

We employ all-atom molecular dynamics simulations along with novel enhanced sampling techniques to characterize the large-scale conformational changes of membrane transporters and their coupling to chemical events. In this project, Blue Waters resources will be used to study the conformational landscape of a bacterial membrane transporter involved in peptide transport. Living cells rely on continuous exchange of molecules across cellular membranes for their normal function. Membrane transporters provide the machinery to intimately couple active transport of materials to various forms of cellular energy. Proton-coupled oligopeptide transporters (POTs), in particular, couple the inwardly directed proton flow to the transport of small peptides and peptide-like molecules. The human POT transporters PepT₁ and PepT₂ provide the main route through which the body absorbs and retains dietary proteins. Human POTs also recognize several important families of peptide-like drug compounds such as β-lactam antibiotics. Employing equilibrium and non-equilibrium simulations, enhanced sampling techniques, and path-finding algorithms, within a novel Riemannian framework, our simulations will characterize the conformational free energy landscape of GkPOT, a homolog of human POTs, in its inward-facing, outward-facing, and intermediate states. A detailed description of GkPOT conformational landscape achieved by our proposed simulations, will shed light on the structure-function relationship in POTs and other membrane transporters.