Sodium/proton antiporters, also known as sodium/proton exchangers, are essential secondary active transporters that are involved in pH homeostasis and regulation of sodium concentration and cell volume. They belong to the monovalent cation/proton antiporter families (CPA1 and CPA2) which all appear to share a common fold, spanning prokaryotic to mammalian family members. We have been using molecular dynamics simulations (long equilibrium MD, free energy calculations, enhanced sampling for rare events, constant pH simulations) in combination with experimental techniques such as X-ray crystallography, cryo-electron microscopy, and functional measurements to better understand the mechanism of transporters in the CPA1 and CPA2 families.  We have been following a research program to dissect key steps in the transport cycle, namely identification of binding sites of ions and substrates, delineation of the moving elements of the alternating access transition, and sampling of the transitions themselves. We employ an analytical multi-scale rate model to combine estimates of rates and free energies from simulations to arrive at a bottom-up computational estimate for the transporter turnover number as function of the external gradients. Experiments and simulations taken together allow us to understand the fundamental physiological process of ion-driven transport across the membrane at the molecular scale.

Structure, dynamics, and function of sodium/proton antiporters and exchangers

ACS Fall 2021

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