Prokaryotic sodium-proton antiporters, such as NhaA from <i>Escherichia coli</i>, are important model systems for understanding the medically relevant human analogs which are drug targets for the treatment of heart diseases. In NhaA there are two proton binding sites, one being Asp164 which is supported by biochemical and biophysical experiments, but the identity of the second proton binding site is a topic of debate. Recent mutagenesis experiments suggest Lys300 may not be the second proton binding residue, as Lys300 mutants remained electrogenic. Here we used continuous constant pH molecular dynamics to investigate the second proton binding site in NhaA.<i> </i>Calculated pKa values of the wild type and mutants (K300A, K300R, and K300Q D163N) suggest that Asp133, a residue close to Asp163 and Asp164, can serve as an alternative proton-binding site in place of Lys300. Together with conformational details, our work supports the salt-bridge model in which Lys300 is a second binding site that participates in electrogenic sodium transport by NhaA.

Resolving a proton-binding site in the sodium-proton antiporter NhaA by continuous constant pH molecular dynamics

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.