Monte Carlo simulation of pH activated conformational changes of coarse-grained sodium-proton antiporters

Sodium-proton antiporters are membrane proteins present throughout the eukaryotic and prokaryotic domains that have a critical role in balancing cell pH and cell volume. The Escherichia coli antiporter NhaA has pH-dependent behavior. There have been many studies regarding the function of this antiporter (Alhadeff and Warshel, PNAS (2015) 112 (40) 12378-12383), but the conformational energy landscape of this system at varying pH is not well-known. In this study, we map the energy landscape between two pH levels for two different conformations of the wild antiporter and a mutated variant using MD with coarse-graining. By Monte Carlo simulation on the energy landscape, we show that the mutated variant changes the stability of the antiporter without blocking the transport, in agreement with experimental results (Calinescu et. al. J. Biol. Chem. (2017) 292(19) 7932–7941).