Ion Binding and Selectivity of the Na+/H+ Antiporter MjNhaP1 from Experiment and Simulation

Cells employ membrane-embedded antiporter proteins to control their pH, salt concentration, and volume. The large family of cation/proton antiporters is dominated by Na+/H+ antiporters that exchange sodium ions against protons, but homologous K+/H+ exchangers have recently been characterized. We sho...

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Published in:The journal of physical chemistry. B 2020-01, Vol.124 (2), p.336-344
Main Authors: Warnau, Judith, Wöhlert, David, Okazaki, Kei-ichi, Yildiz, Özkan, Gamiz-Hernandez, Ana P, Kaila, Ville R. I, Kühlbrandt, Werner, Hummer, Gerhard
Format: Article
Language:English
Subjects:
Archaeal Proteins - chemistry
Archaeal Proteins - genetics
Archaeal Proteins - metabolism
Binding Sites
Methanocaldococcus - chemistry
Molecular Dynamics Simulation
Mutation
Potassium - metabolism
Protein Binding
Protein Conformation
Sodium - metabolism
Sodium-Hydrogen Exchangers - chemistry
Sodium-Hydrogen Exchangers - genetics
Sodium-Hydrogen Exchangers - metabolism
Thermodynamics
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Summary:Cells employ membrane-embedded antiporter proteins to control their pH, salt concentration, and volume. The large family of cation/proton antiporters is dominated by Na+/H+ antiporters that exchange sodium ions against protons, but homologous K+/H+ exchangers have recently been characterized. We show experimentally that the electroneutral antiporter NhaP1 of Methanocaldococcus jannaschii (MjNhaP1) is highly selective for Na+ ions. We then characterize the ion selectivity in both the inward-open and outward-open states of MjNhaP1 using classical molecular dynamics simulations, free energy calculations, and hybrid quantum/classical (QM/MM) simulations. We show that MjNhaP1 is highly selective for binding of Na+ over K+ in the inward-open state, yet it is only weakly selective in the outward-open state. These findings are consistent with the function of MjNhaP1 as a sodium-driven deacidifier of the cytosol that maintains a high cytosolic K+ concentration in environments of high salinity. By combining experiment and computation, we gain mechanistic insight into the Na+/H+ transport mechanism and help elucidate the molecular basis for ion selectivity in cation/proton exchangers.
ISSN:1520-6106
1520-5207
1520-5207
DOI:10.1021/acs.jpcb.9b08552