细菌电压门控钠通道的选择性过滤器的质子化状态是由离子调节的

A. Damjanovic, Ada Y. Chen, R. Rosenberg, D. Roe, Xiongwu Wu, B. Brooks
{"title":"细菌电压门控钠通道的选择性过滤器的质子化状态是由离子调节的","authors":"A. Damjanovic, Ada Y. Chen, R. Rosenberg, D. Roe, Xiongwu Wu, B. Brooks","doi":"10.1002/prot.25831","DOIUrl":null,"url":null,"abstract":"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. (NavMs) 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.","PeriodicalId":20789,"journal":{"name":"Proteins: Structure","volume":"73 1","pages":"527 - 539"},"PeriodicalIF":0.0000,"publicationDate":"2020-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"7","resultStr":"{\"title\":\"Protonation state of the selectivity filter of bacterial voltage‐gated sodium channels is modulated by ions\",\"authors\":\"A. Damjanovic, Ada Y. Chen, R. Rosenberg, D. Roe, Xiongwu Wu, B. Brooks\",\"doi\":\"10.1002/prot.25831\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"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. (NavMs) 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.\",\"PeriodicalId\":20789,\"journal\":{\"name\":\"Proteins: Structure\",\"volume\":\"73 1\",\"pages\":\"527 - 539\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2020-03-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"7\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Proteins: Structure\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1002/prot.25831\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Proteins: Structure","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1002/prot.25831","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 7

摘要

细菌电压门控钠通道的选择性过滤器(SF)由四个以C4对称排列的谷氨酸残基组成。这个四分体的质子化状态种群尚不清楚。为了解决这个问题,我们在显式溶剂和自由能微扰计算中,通过恒定pH方法模拟了磁球菌(Magnetococcus sp., NavMs)细菌电压门控钠通道的孔域。我们发现,在生理pH下,SF的完全去质子化以及单质子化和双质子化状态似乎是可行的,并且计算的pKa随着每增加一个结合离子而降低,这表明孔中离子数量的减少可以导致SF的质子化。先前的分子动力学模拟表明,质子化可以导致电导的降低,但没有进行pKa计算。我们证实了质子化使孔隙中的离子数量减少,并观察到质子化引起的结构对称性破坏;去质子化通道的SF最接近开态晶体结构中的C4对称性,而质子化通道的SF表现出更大程度的不对称性,这可能导致晶体结构中具有C2对称性的失活状态的过渡。我们推测,由于随机波动或传导导致的离子耗尽,通道口附近离子数量的减少可能是一种自我调节机制,导致在功能上类似于失活状态的非导电状态。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Protonation state of the selectivity filter of bacterial voltage‐gated sodium channels is modulated by ions
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. (NavMs) 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.
求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
自引率
0.00%
发文量
0
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信