Mechanistic Picture for Chemomechanical Coupling in a Bacterial Proton-Coupled Oligopeptide Transporter from Streptococcus Thermophilus
by Immadisetty, K.; Moradi, M.
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.
- Journal
- Journal of Physical Chemistry B
- Volume
- 125
- Issue
- 34
- Year
- 2021
- Start Page
- 9738-9750
- URL
- https://dx.doi.org/10.1021/acs.jpcb.1c03982
- ISBN/ISSN
- 1520-5207; 1520-6106
- DOI
- 10.1021/acs.jpcb.1c03982