Mechanism of the electroneutral sodium/proton antiporter PaNhaP from transition-path shooting

Kei-ichi Okazaki (), David Wöhlert, Judith Warnau, Hendrik Jung, Özkan Yildiz, Werner Kühlbrandt and Gerhard Hummer ()
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Kei-ichi Okazaki: National Institutes of Natural Sciences
David Wöhlert: Max Planck Institute of Biophysics
Judith Warnau: Max Planck Institute of Biophysics
Hendrik Jung: Max Planck Institute of Biophysics
Özkan Yildiz: Max Planck Institute of Biophysics
Werner Kühlbrandt: Max Planck Institute of Biophysics
Gerhard Hummer: Max Planck Institute of Biophysics

Nature Communications, 2019, vol. 10, issue 1, 1-10

Abstract: Abstract Na+/H+ antiporters exchange sodium ions and protons on opposite sides of lipid membranes. The electroneutral Na+/H+ antiporter NhaP from archaea Pyrococcus abyssi (PaNhaP) is a functional homolog of the human Na+/H+ exchanger NHE1, which is an important drug target. Here we resolve the Na+ and H+ transport cycle of PaNhaP by transition-path sampling. The resulting molecular dynamics trajectories of repeated ion transport events proceed without bias force, and overcome the enormous time-scale gap between seconds-scale ion exchange and microseconds simulations. The simulations reveal a hydrophobic gate to the extracellular side that opens and closes in response to the transporter domain motion. Weakening the gate by mutagenesis makes the transporter faster, suggesting that the gate balances competing demands of fidelity and efficiency. Transition-path sampling and a committor-based reaction coordinate optimization identify the essential motions and interactions that realize conformational alternation between the two access states in transporter function.

Date: 2019
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DOI: 10.1038/s41467-019-09739-0

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