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Computational Tools for Interpreting Ion Channel pH-Dependence
Activity in many biological systems is mediated by pH, involving proton titratable groups with pKas in the relevant pH range. Experimental analysis of pH-dependence in proteins focusses on particular sidechains, often with mutagenesis of histidine, due to its pKa near to neutral pH. The key question...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4411139/ https://www.ncbi.nlm.nih.gov/pubmed/25915903 http://dx.doi.org/10.1371/journal.pone.0125293 |
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author | Sazanavets, Ivan Warwicker, Jim |
author_facet | Sazanavets, Ivan Warwicker, Jim |
author_sort | Sazanavets, Ivan |
collection | PubMed |
description | Activity in many biological systems is mediated by pH, involving proton titratable groups with pKas in the relevant pH range. Experimental analysis of pH-dependence in proteins focusses on particular sidechains, often with mutagenesis of histidine, due to its pKa near to neutral pH. The key question for algorithms that predict pKas is whether they are sufficiently accurate to effectively narrow the search for molecular determinants of pH-dependence. Through analysis of inwardly rectifying potassium (Kir) channels and acid-sensing ion channels (ASICs), mutational effects on pH-dependence are probed, distinguishing between groups described as pH-coupled or pH-sensor. Whereas mutation can lead to a shift in transition pH between open and closed forms for either type of group, only for pH-sensor groups does mutation modulate the amplitude of the transition. It is shown that a hybrid Finite Difference Poisson-Boltzmann (FDPB) – Debye-Hückel continuum electrostatic model can filter mutation candidates, providing enrichment for key pH-coupled and pH-sensor residues in both ASICs and Kir channels, in comparison with application of FDPB alone. |
format | Online Article Text |
id | pubmed-4411139 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-44111392015-05-07 Computational Tools for Interpreting Ion Channel pH-Dependence Sazanavets, Ivan Warwicker, Jim PLoS One Research Article Activity in many biological systems is mediated by pH, involving proton titratable groups with pKas in the relevant pH range. Experimental analysis of pH-dependence in proteins focusses on particular sidechains, often with mutagenesis of histidine, due to its pKa near to neutral pH. The key question for algorithms that predict pKas is whether they are sufficiently accurate to effectively narrow the search for molecular determinants of pH-dependence. Through analysis of inwardly rectifying potassium (Kir) channels and acid-sensing ion channels (ASICs), mutational effects on pH-dependence are probed, distinguishing between groups described as pH-coupled or pH-sensor. Whereas mutation can lead to a shift in transition pH between open and closed forms for either type of group, only for pH-sensor groups does mutation modulate the amplitude of the transition. It is shown that a hybrid Finite Difference Poisson-Boltzmann (FDPB) – Debye-Hückel continuum electrostatic model can filter mutation candidates, providing enrichment for key pH-coupled and pH-sensor residues in both ASICs and Kir channels, in comparison with application of FDPB alone. Public Library of Science 2015-04-27 /pmc/articles/PMC4411139/ /pubmed/25915903 http://dx.doi.org/10.1371/journal.pone.0125293 Text en © 2015 Sazanavets, Warwicker http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Sazanavets, Ivan Warwicker, Jim Computational Tools for Interpreting Ion Channel pH-Dependence |
title | Computational Tools for Interpreting Ion Channel pH-Dependence |
title_full | Computational Tools for Interpreting Ion Channel pH-Dependence |
title_fullStr | Computational Tools for Interpreting Ion Channel pH-Dependence |
title_full_unstemmed | Computational Tools for Interpreting Ion Channel pH-Dependence |
title_short | Computational Tools for Interpreting Ion Channel pH-Dependence |
title_sort | computational tools for interpreting ion channel ph-dependence |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4411139/ https://www.ncbi.nlm.nih.gov/pubmed/25915903 http://dx.doi.org/10.1371/journal.pone.0125293 |
work_keys_str_mv | AT sazanavetsivan computationaltoolsforinterpretingionchannelphdependence AT warwickerjim computationaltoolsforinterpretingionchannelphdependence |