Simulating the function of sodium/proton antiporters

The molecular basis of the function of transporters is a problem of significant importance, where the emerging structural information has not yet been converted to a full understanding of the corresponding function. This work explores the molecular origin of the function of the bacterial Na+/H+ antiporter NhaA by evaluating the energetics of the Na+ and H+ movement and then using the resulting landscape in Monte Carlo (MC) simulations that examine two transport models and explore which model can reproduce the relevant experimental results. The simulations reproduce the observed transport features, by a relatively simple model that relates the protein structure to its transporting function. Focusing on the two key aspartic acid residues of NhaA, D163 and D164, it is found that the fully charged state acts as a Na+ trap, while the fully protonated one poses an energetic barrier which blocks the transport of Na+. It is through alternation between the former and latter states, mediated by the partially protonated protein, that Na+ and protons can be exchanged across the membrane, at 1:2 stoichiometry. Our study provides a numerical validation of the need of large conformational changes for effective transport. Furthermore, we also provide reasonable explanation for the fact that some mammalian transporters have 1:1 stoichiometry. The present coarse-grained model can provide a general way for exploring the function of transporters on a molecular level.