Proton coupling and the multiscale kinetic mechanism of a peptide transporter
Abstract
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.
Additional Information
© 2022 Biophysical Society. Received 24 February 2022, Accepted 19 May 2022, Available online 25 May 2022, Version of Record 21 June 2022. This research was supported by the National Institute of General Medical Sciences (NIGMS) of the US National Institutes of Health (NIH) through grant R01 GM053148. Computational resources were provided by the Research Computing Center (RCC) at the University of Chicago. Author contributions: G.A.V. and S.N. conceptualized and supervised the project. C.L. and Z.Y. performed and analyzed all MD simulations. C.L., Z.Y., S.N., and G.A.V. wrote the manuscript. The authors declare no competing interests.Attached Files
Submitted - 2021.09.10.459748v3.full.pdf
Supplemental Material - 1-s2.0-S0006349522004222-mmc1.pdf
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Additional details
- PMCID
- PMC9279349
- Eprint ID
- 115052
- Resolver ID
- CaltechAUTHORS:20220607-425249000
- R01 GM053148
- NIH
- Created
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2022-06-08Created from EPrint's datestamp field
- Updated
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2022-08-15Created from EPrint's last_modified field