Protonation state of the selectivity filter of bacterial voltage‐gated sodium channels is modulated by ions
| Autor: | Ana Damjanović, Xiongwu Wu, Daniel R. Roe, Ada Y. Chen, Bernard R. Brooks, Robert L Rosenberg |
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| Rok vydání: | 2019 |
| Předmět: |
Protein Conformation
alpha-Helical Population Ionic bonding Protonation Voltage-Gated Sodium Channels Crystal structure Molecular Dynamics Simulation Crystallography X-Ray Biochemistry Ion Free energy perturbation 03 medical and health sciences Deprotonation Bacterial Proteins Structural Biology Protein Interaction Domains and Motifs education Molecular Biology Alphaproteobacteria 030304 developmental biology 0303 health sciences education.field_of_study Binding Sites Ion Transport Chemistry Sodium 030302 biochemistry & molecular biology Conductance Cations Monovalent Hydrogen-Ion Concentration Kinetics Chemical physics Thermodynamics Protons Protein Binding |
| Zdroj: | Proteins: Structure, Function, and Bioinformatics. 88:527-539 |
| ISSN: | 1097-0134 0887-3585 |
| DOI: | 10.1002/prot.25831 |
| Popis: | The selectivity filter (SF) of bacterial voltage-gated sodium channels consists of four glutamate residues arranged in a C4 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. (Nav 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 C4 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 C2 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. |
| Databáze: | OpenAIRE |
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