Conformational change and substrate binding to the bile acid transporter ASBT$_{\mathrm{NM}}$

ORAL

Abstract

The apical sodium-dependant bile acid transporter (ASBT) utilises the sodium gradient to drive the reabsorption of bile acids from the intestine, operating through an alternating-access mechanism. It is of interest as a potential target for the treatment of hypercholesterolemia as well as for drug delivery. Structures of bacterial homologues, including that from Neisseria meningitidis (ASBT$_{\mathrm{NM}})$ in an inward-facing conformation with sodium and the bile acid taurocholate bound, are available. However, less is known about the more dynamic details, including those involving substrate binding and the nature of the conformational transition. We have used molecular dynamics simulations to investigate the behaviour of ASBT$_{\mathrm{NM}}$ on an atomistic scale. Metadynamics was used to explore the inward-outward transition and the binding landscape of taurocholate and sodium to inward facing ASBT$_{\mathrm{NM}}$, with refinement using bias-exchange umbrella sampling to quantify the latter, characterising both the main and alternate binding sites. Together, these results represent an important step towards understanding the complete transport cycle of ASBT.

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Authors

  • Fiona Naughton

    Arizona State University

  • Barry Ritchie

    University of New Mexico, Ion Linac Systems, Tech-X Corporation, Los Alamos National Laboratory, Ronald Reagan UCLA Medical Center, Brigham Young University, Brigham Young University - Provo, United States Air Force Academy, university of Michigan, SISSA, Trieste, Stanford University, Worcester Polytechnic Institute, Grinnell College, Department of Physics, Arizona State University, Brookhaven National Laboratory, University of Southern California, Argonne National Laboratory, Department of Electrical and Computer Engineering, University of New Mexico, Department of Electrical and Computer Engineering and Department of Mechanical Engineering, University of New Mexico, Lock Haven University, Illinois State University, Department of Physics, Utah State University, Logan, Utah, 84322, Department of Physics, New Mexico State University, Las Cruces, New Mexico 88003, USA, Department of Materials, Devices, and Energy Technologies, Sandia National Laboratories, Albuquerque, New Mexico 87185, USA, Kyoto University, University of Guadalajara, University of Florida, Embry-Riddle Aeronautical University, Air Force Research Laboratory, Space Vehicles Directorate, Assurance Technology Corporation, Carlisle, MA, Georgia Tech Research Institute, Atlanta, GA, Utah State University, Georgia Institute of Technology, University of Tennessee, Knoxville, Arizona State University, Department of Physics, United States Air Force Academy, 80840 USAFA, CO, USA, Shaffer Consulting Inc, Max Planck Institute for Astrophysics, Harvard University, Max Planck Institute for Gravitational Physics, Albert Einstein Institute, ASU