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J Biol Chem. 2017 Jul 28;292(30):12412-12423. doi: 10.1074/jbc.M117.779090. Epub 2017 Jun 6.

Molecular simulations and free-energy calculations suggest conformation-dependent anion binding to a cytoplasmic site as a mechanism for Na+/K+-ATPase ion selectivity.

Author information

From the Department of Chemistry and.
Institute for Computational Molecular Science, Temple University, Philadelphia, Pennsylvania 19122.
Science for Life Laboratory, Department of Theoretical Physics, KTH Royal Institute of Technology, Stockholm 11428, Sweden, and.
the Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers University, Newark, New Jersey 07103.
From the Department of Chemistry and
From the Department of Chemistry and


Na+/K+-ATPase transports Na+ and K+ ions across the cell membrane via an ion-binding site becoming alternatively accessible to the intra- and extracellular milieu by conformational transitions that confer marked changes in ion-binding stoichiometry and selectivity. To probe the mechanism of these changes, we used molecular simulation and free-energy perturbation approaches to identify probable protonation states of Na+- and K+-coordinating residues in E1P and E2P conformations of Na+/K+-ATPase. Analysis of these simulations revealed a molecular mechanism responsible for the change in protonation state: the conformation-dependent binding of an anion (a chloride ion in our simulations) to a previously unrecognized cytoplasmic site in the loop between transmembrane helices 8 and 9, which influences the electrostatic potential of the crucial Na+-coordinating residue Asp926 This mechanistic model is consistent with experimental observations and provides a molecular-level picture of how E1P to E2P enzyme conformational transitions are coupled to changes in ion-binding stoichiometry and selectivity.


Na+/K+-ATPase; anion binding site; free energy perturbation; membrane transport; membrane transporter; molecular dynamics; potassium transport; protonation; selectivity; sodium transport

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