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Multiscale Kinetic Modeling Reveals an Ensemble of Cl(–)/H(+) Exchange Pathways in ClC-ec1 Antiporter
[Image: see text] 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 multis...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical
Society
2018
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5812667/ https://www.ncbi.nlm.nih.gov/pubmed/29332400 http://dx.doi.org/10.1021/jacs.7b11463 |
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author | Mayes, Heather B. Lee, Sangyun White, Andrew D. Voth, Gregory A. Swanson, Jessica M. J. |
author_facet | Mayes, Heather B. Lee, Sangyun White, Andrew D. Voth, Gregory A. Swanson, Jessica M. J. |
author_sort | Mayes, Heather B. |
collection | PubMed |
description | [Image: see text] 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. |
format | Online Article Text |
id | pubmed-5812667 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | American Chemical
Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-58126672018-02-16 Multiscale Kinetic Modeling Reveals an Ensemble of Cl(–)/H(+) Exchange Pathways in ClC-ec1 Antiporter Mayes, Heather B. Lee, Sangyun White, Andrew D. Voth, Gregory A. Swanson, Jessica M. J. J Am Chem Soc [Image: see text] 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. American Chemical Society 2018-01-14 2018-02-07 /pmc/articles/PMC5812667/ /pubmed/29332400 http://dx.doi.org/10.1021/jacs.7b11463 Text en Copyright © 2018 American Chemical Society This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) , which permits copying and redistribution of the article or any adaptations for non-commercial purposes. |
spellingShingle | Mayes, Heather B. Lee, Sangyun White, Andrew D. Voth, Gregory A. Swanson, Jessica M. J. Multiscale Kinetic Modeling Reveals an Ensemble of Cl(–)/H(+) Exchange Pathways in ClC-ec1 Antiporter |
title | Multiscale
Kinetic Modeling Reveals an Ensemble of
Cl(–)/H(+) Exchange Pathways in ClC-ec1 Antiporter |
title_full | Multiscale
Kinetic Modeling Reveals an Ensemble of
Cl(–)/H(+) Exchange Pathways in ClC-ec1 Antiporter |
title_fullStr | Multiscale
Kinetic Modeling Reveals an Ensemble of
Cl(–)/H(+) Exchange Pathways in ClC-ec1 Antiporter |
title_full_unstemmed | Multiscale
Kinetic Modeling Reveals an Ensemble of
Cl(–)/H(+) Exchange Pathways in ClC-ec1 Antiporter |
title_short | Multiscale
Kinetic Modeling Reveals an Ensemble of
Cl(–)/H(+) Exchange Pathways in ClC-ec1 Antiporter |
title_sort | multiscale
kinetic modeling reveals an ensemble of
cl(–)/h(+) exchange pathways in clc-ec1 antiporter |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5812667/ https://www.ncbi.nlm.nih.gov/pubmed/29332400 http://dx.doi.org/10.1021/jacs.7b11463 |
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