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首页> 美国卫生研究院文献>The Journal of General Physiology >Molecular dynamics simulations of the Cx26 hemichannel: Evaluation of structural models with Brownian dynamics
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Molecular dynamics simulations of the Cx26 hemichannel: Evaluation of structural models with Brownian dynamics

机译：Cx26半通道的分子动力学模拟：利用布朗动力学评估结构模型

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The recently published crystal structure of the Cx26 gap junction channel provides a unique opportunity for elucidation of the structure of the conductive connexin pore and the molecular determinants of its ion permeation properties (conductance, current–voltage [I-V] relations, and charge selectivity). However, the crystal structure was incomplete, most notably lacking the coordinates of the N-terminal methionine residue, which resides within the pore, and also lacking two cytosolic domains. To allow computational studies for comparison with the known channel properties, we completed the structure. Grand canonical Monte Carlo Brownian dynamics (GCMC/BD) simulations of the completed and the published Cx26 hemichannel crystal structure indicate that the pore is too narrow to permit significant ion flux. The GCMC/BD simulations predict marked inward current rectification and almost perfect anion selectivity, both inconsistent with known channel properties. The completed structure was refined by all-atom molecular dynamics (MD) simulations (220 ns total) in an explicit solvent and POPC membrane system. These MD simulations produced an equilibrated structure with a larger minimal pore diameter, which decreased the height of the permeation barrier formed by the N terminus. GCMC/BD simulations of the MD-equilibrated structure yielded more appropriate single-channel conductance and less anion/cation selectivity. However, the simulations much more closely matched experimentally determined I-V relations when the charge effects of specific co- and posttranslational modifications of Cx26 previously identified by mass spectrometry were incorporated. We conclude that the average equilibrated structure obtained after MD simulations more closely represents the open Cx26 hemichannel structure than does the crystal structure, and that co- and posttranslational modifications of Cx26 hemichannels are likely to play an important physiological role by defining the conductance and ion selectivity of Cx26 channels. Furthermore, the simulations and data suggest that experimentally observed heterogeneity in Cx26 I-V relations can be accounted for by variation in co- and posttranslational modifications.
机译：最近发布的Cx26间隙连接通道的晶体结构为阐明导电连接蛋白孔的结构及其离子渗透特性（电导率，电流-电压[I-V]关系和电荷选择性）的分子决定因素提供了独特的机会。然而，晶体结构是不完整的，最明显的是缺少位于孔中的N-末端甲硫氨酸残基的坐标，并且还缺少两个胞质结构域。为了允许进行计算研究以与已知通道属性进行比较，我们完成了结构。对已完成和已发布的Cx26半通道晶体结构进行的大正则蒙特卡罗布朗动力学（GCMC / BD）模拟表明，孔太窄，无法产生明显的离子通量。 GCMC / BD模拟预测显着的内向电流整流和几乎完美的阴离子选择性，两者均与已知通道特性不一致。在明确的溶剂和POPC膜系统中，通过全原子分子动力学（MD）模拟（总计220 ns）完善了完整的结构。这些MD模拟产生了具有更大最小孔径的平衡结构，从而减小了由N末端形成的渗透屏障的高度。 MD平衡结构的GCMC / BD模拟产生更合适的单通道电导和更少的阴离子/阳离子选择性。但是，当结合了先前由质谱法鉴定的Cx26的特定共翻译和翻译后修饰的电荷效应时，模拟与实验确定的I-V关系更加紧密匹配。我们得出结论，MD模拟后获得的平均平衡结构比晶体结构更能代表开放的Cx26半通道结构，并且Cx26半通道的共翻译和翻译后修饰很可能通过定义电导率和离子选择性而起重要的生理作用。 Cx26通道。此外，模拟和数据表明，通过共同翻译和翻译后修饰的变化可以解释Cx26 I-V关系中实验观察到的异质性。

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