Journal article
Protonation state of the selectivity filter of bacterial voltage-gated sodium channels is modulated by ions
Proteins, structure, function, and bioinformatics, v 88(3), pp 527-539
Mar 2020
PMID: 31589792
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The selectivity filter (SF) of bacterial voltage-gated sodium channels consists of four glutamate residues arranged in a C
symmetry. The protonation state population of this tetrad is unclear. To address this question, we simulate the pore domain of bacterial voltage-gated sodium channel of Magnetococcus sp. (Na
Ms) through constant pH methodology in explicit solvent and free energy perturbation calculations. We find that at physiological pH the fully deprotonated as well as singly and doubly protonated states of the SF appear feasible, and that the calculated pKa decreases with each additional bound ion, suggesting that a decrease in the number of ions in the pore can lead to protonation of the SF. Previous molecular dynamics simulations have suggested that protonation can lead to a decrease in the conductance, but no pKa calculations were performed. We confirm a decreased ionic population of the pore with protonation, and also observe structural symmetry breaking triggered by protonation; the SF of the deprotonated channel is closest to the C
symmetry observed in crystal structures of the open state, while the SF of protonated states display greater levels of asymmetry which could lead to transition to the inactivated state which possesses a C
symmetry in the crystal structure. We speculate that the decrease in the number of ions near the mouth of the channel, due to either random fluctuations or ion depletion due to conduction, could be a self-regulatory mechanism resulting in a nonconducting state that functionally resembles inactivated states.
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Details
- Title
- Protonation state of the selectivity filter of bacterial voltage-gated sodium channels is modulated by ions
- Creators
- Ana Damjanovic - Johns Hopkins UniversityAda Y Chen - Johns Hopkins UniversityRobert L Rosenberg - Earlham CollegeDaniel R Roe - National Heart Lung and Blood InstituteXiongwu Wu - National Heart Lung and Blood InstituteBernard R Brooks - National Institutes of Health
- Publication Details
- Proteins, structure, function, and bioinformatics, v 88(3), pp 527-539
- Publisher
- Wiley
- Grant note
- HHSN268201800026P / NHLBI NIH HHS HHSN268201500032P / NHLBI NIH HHS ZIA HL001050-22 / NHLBI NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:000495906500001
- Scopus ID
- 2-s2.0-85074993598
- Other Identifier
- 991021903310104721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Biophysics