期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 140, 期 5, 页码 1793-1804出版社
AMER CHEMICAL SOC
DOI: 10.1021/jacs.7b11463
关键词
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资金
- National Institutes of Health (NIH) [R01-GM053148]
- National Science Foundation [ACI-1053575]
- U.S. Department of Defense (DOD) High Performance Computing Modernization Program at the Engineer Research and Development Center (ERDC)
- Navy DOD Super computing Resource Centers
- University of Chicago Research Computing Center (RCC)
- NIH
- Argonne National Laboratory [1S10OD018495-01]
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM053148] Funding Source: NIH RePORTER
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 pK(a) 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.
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