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PreprintCited by 8Protein Structure and DynamicsDrug Transport and Resistance MechanismsIon Transport and Channel Regulation

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Molecular mechanism of Na + /H + antiporting in NhaA

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Xie, Tengyu, He, Jiahao, Sun, Shuo, Chen, Yulei, Huang, Jing, Huang, Yandong·2024·Journal of Chemical Theory and Computation
DOI 10.1101/2024.11.23.624977

Preprint — published as 10.1021/acs.jctc.5c00632

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Abstract

Sodium-proton antiporter NhaA of Escherichia coli is a paradigm to investigate the mechanistic basis of the fundamental Na + /H + exchange in cells. However, all existing crystal structures of NhaA are inward-facing (IF) and the putative outward-facing (OF) structures are still unsolved by experiment, limiting a complete understanding of the transport cycle where Lys300 plays a key role in both structural stability and transport function. Here, we report a set of regular molecular dynamics (MD) simulations that start from the structure predicted by an artificial intelligence method that generates function-relevant alternative conformations. It is found that NhaA rapidly relaxes into either the IF or OF conformation. Further-more, neutralization of Lys300 allows two sodium ions bound to the reaction cavity, which is associated with enhanced conformational sampling. Based on these observations, we propose a sodium-coupled mechanism of Na + /H + antiporting.

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Metadata

Authors
Xie, T., He, J., Sun, S., Chen, Y., Huang, J., & Huang, Y.
Affiliations
  • Westlake University (CN)
  • Jimei University (CN)
Corresponding author
Huang, Yandong
ORCID
Venue
Journal of Chemical Theory and Computation
Publisher
openRxiv
Published
2024-11-25
Volume
21
Issue
18
Pages
9107-9119
ISSN
1549-9618 (ISSN-L)
DOI
10.1101/2024.11.23.624977
OpenAlex
W4413908476
Cited by
8
References
1
Citations by year
2026: 7 · 2025: 1
FWCI
2.42
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Chemical Theory and Computation (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • National Natural Science Foundation of China (11804114, 32171247)
  • Natural Science Foundation of Fujian Province (2023J01329)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
Keywords
NhaA, Escherichia coli, Na+/H+ exchange, outward-facing conformation, inward-facing conformation, sodium ion binding, conformational sampling, molecular dynamics simulation
MeSH terms
Escherichia coli, Protein Conformation, Sodium, Sodium-Hydrogen Exchangers, Escherichia coli Proteins, Molecular Dynamics Simulation

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