Journal
JOURNAL OF PHYSICAL CHEMISTRY B
Volume 125, Issue 34, Pages 9738-9750Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jpcb.1c03982
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Funding
- National Science Foundation [CHE 1945465, OCI-0725070, ACI-1238993, ACI-1548562]
- Arkansas Biosciences Institute
- state of Illinois
- Arkansas High Performance Computing Center
- Arkansas Economic Development Commission
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This study used microsecond-level molecular dynamics simulations to investigate the conformational changes and substrate transport mechanisms in proton-coupled oligopeptide transporters (POTs), shedding light on the structure-function relationship in this important family of transporters.
Proton-coupled oligopeptide transporters (POTs) use the proton electrochemical gradient to transport peptides across the cell membrane. Despite the significant biological and biomedical relevance of these proteins, a detailed mechanistic picture for chemomechanical couplings involved in substrate/proton transport and protein structural changes is missing. Therefore, we performed microsecond-level molecular dynamics simulations of bacterial POT PepT(St), which shares similar to 80% sequence identity with the human POT, PepT1, in the substrate-binding region. Three different conformational states of PepTSt were simulated, including (i) occluded, apo, (ii) inward-facing, apo, and (iii) inward-facing(occluded), Leu-Ala bound. We propose that the interaction of R33 with E299 and E300 acts as a conformational switch (i.e., to trigger the conformational change from an inward- to outward-facing state) in the substrate transport. Additionally, we propose that E299 and E400 disengage from interacting with the substrate either through protonation or through coordination with a cation for the substrate to get transported. This study provides clues to understand the chemomechanical couplings in POTs and paves the way to decipher the molecular-level underpinnings of the structure-function relationship in this important family of transporters.
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