Role of Hydration and Amino Acid Interactions on the Ion Permeation Mechanism in the hNaV1.5 Channel.

IF 2.9 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Biochemistry Biochemistry Pub Date : 2025-01-07 Epub Date: 2024-12-17 DOI:10.1021/acs.biochem.4c00664
Nuria Anguita-Ortiz, Juan J Nogueira
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引用次数: 0

Abstract

This study explores the ion selectivity and conduction mechanisms of the hNaV1.5 sodium channel using classical molecular dynamics simulations under an externally applied electric field. Our findings reveal distinct conduction mechanisms for Na+ and K+, primarily driven by differences in their hydration states when they diffuse close to the channel's selective filter (DEKA) and extracellular ring (EEDD). The Na+ ions undergo partial dehydration in the EEDD region, followed by a rehydration step in the DEKA ring, resulting in longer retention times and a deeper free energy minimum compared to K+. Conversely, the K+ ions exhibit a continuous dehydration process, facilitating a smoother passage through these key regions. These results indicate that ion selectivity and conductance are primarily governed by solvation dynamics, which, in turn, depend on the interactions with key charged residues within the channel. Additionally, we show that the delicate energetic balance between the interactions of the ions with the protein residues and with their solvation shells during the dehydration and rehydration processes is not properly captured by the force field. As a consequence, the selectivity of the channel is not well described, indicating that more accurate computational models must be applied to simulate ion conduction through eukaryotic NaV channels.

水合作用和氨基酸相互作用在hNaV1.5通道离子渗透机制中的作用。
本研究利用经典分子动力学模拟方法探讨了在外加电场作用下hNaV1.5钠离子通道的离子选择性和传导机制。我们的研究结果揭示了Na+和K+的不同传导机制,主要是由于它们在通道的选择性过滤器(DEKA)和细胞外环(EEDD)附近扩散时水合状态的差异。与K+相比,Na+离子在edd区域经历部分脱水,随后在DEKA环中进行再水化步骤,导致保留时间更长,自由能最小值更高。相反,K+离子表现出连续的脱水过程,有助于更顺利地通过这些关键区域。这些结果表明,离子的选择性和电导率主要由溶剂化动力学决定,而溶剂化动力学又取决于离子与通道内关键带电残基的相互作用。此外,我们表明,在脱水和再水化过程中,离子与蛋白质残基及其溶剂化壳的相互作用之间的微妙能量平衡并没有被力场适当地捕获。因此,通道的选择性没有得到很好的描述,这表明必须应用更精确的计算模型来模拟通过真核生物NaV通道的离子传导。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Biochemistry Biochemistry
Biochemistry Biochemistry 生物-生化与分子生物学
CiteScore
5.50
自引率
3.40%
发文量
336
审稿时长
1-2 weeks
期刊介绍: Biochemistry provides an international forum for publishing exceptional, rigorous, high-impact research across all of biological chemistry. This broad scope includes studies on the chemical, physical, mechanistic, and/or structural basis of biological or cell function, and encompasses the fields of chemical biology, synthetic biology, disease biology, cell biology, nucleic acid biology, neuroscience, structural biology, and biophysics. In addition to traditional Research Articles, Biochemistry also publishes Communications, Viewpoints, and Perspectives, as well as From the Bench articles that report new methods of particular interest to the biological chemistry community.
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