Proton coupling and the multiscale kinetic mechanism of a peptide transporter

Biophys J. 2022 Jun 21;121(12):2266-2278. doi: 10.1016/j.bpj.2022.05.029. Epub 2022 May 25.


Proton-coupled peptide transporters (POTs) are crucial for the uptake of di- and tripeptides as well as drug and prodrug molecules in prokaryotes and eukaryotic cells. We illustrate from multiscale modeling how transmembrane proton flux couples within a POT protein to drive essential steps of the full functional cycle: 1) protonation of a glutamate on transmembrane helix 7 (TM7) opens the extracellular gate, allowing ligand entry; 2) inward proton flow induces the cytosolic release of ligand by varying the protonation state of a second conserved glutamate on TM10; 3) proton movement between TM7 and TM10 is thermodynamically driven and kinetically permissible via water proton shuttling without the participation of ligand. Our results, for the first time, give direct computational confirmation for the alternating access model of POTs, and point to a quantitative multiscale kinetic picture of the functioning protein mechanism.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Glutamic Acid
  • Ligands
  • Membrane Transport Proteins* / metabolism
  • Peptides / metabolism
  • Protons*


  • Ligands
  • Membrane Transport Proteins
  • Peptides
  • Protons
  • Glutamic Acid
  • peptide permease