3 years ago

Multiscale Kinetic Modeling Reveals an Ensemble of Cl–/H+ Exchange Pathways in ClC-ec1 Antiporter

Multiscale
Kinetic Modeling Reveals an Ensemble of
Cl–/H+ Exchange Pathways in ClC-ec1 Antiporter
Sangyun Lee, Jessica M. J. Swanson, Gregory A. Voth, Heather B. Mayes, Andrew D. White
Despite several years of research, the ion exchange mechanisms in chloride/proton antiporters and many other coupled transporters are not yet understood at the molecular level. Here, we present a novel approach to kinetic modeling and apply it to ion exchange in ClC-ec1. Our multiscale kinetic model is developed by (1) calculating the state-to-state rate coefficients with reactive and polarizable molecular dynamics simulations, (2) optimizing these rates in a global kinetic network, and (3) predicting new electrophysiological results. The model shows that the robust Cl:H exchange ratio (2.2:1) can indeed arise from kinetic coupling without large protein conformational changes, indicating a possible facile evolutionary connection to chloride channels. The E148 amino acid residue is shown to couple chloride and proton transport through protonation-dependent blockage of the central anion binding site and an anion-dependent pKa value, which influences proton transport. The results demonstrate how an ensemble of different exchange pathways, as opposed to a single series of transitions, culminates in the macroscopic observables of the antiporter, such as transport rates, chloride/proton stoichiometry, and pH dependence.

Publisher URL: http://dx.doi.org/10.1021/jacs.7b11463

DOI: 10.1021/jacs.7b11463

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