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首页> 外文期刊>Biochemistry >Dynamics, hydration, and motional averaging of a loop-gated artificial protein cavity: The W191G mutant of cytochrome c peroxidase in water as revealed by molecular dynamics simulations
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Dynamics, hydration, and motional averaging of a loop-gated artificial protein cavity: The W191G mutant of cytochrome c peroxidase in water as revealed by molecular dynamics simulations

机译：动态，水合和运动平均的环门人工蛋白质腔：分子动力学模拟显示水中的细胞色素C过氧化物酶的W191G突变体

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Five molecular dynamics simulations of the W191G cavity mutant of cytochrome c peroxidase in explicit water reveal distinct dynamic and hydration behavior depending on the closed or open state of the flexible loop gating the cavity, the binding of (K+ or small molecule) cations, and the system temperature. The conformational spaces sampled by the loop region and by the cavity significantly reduce upon binding. The largest ordering factor on water dynamics is the presence of the K+ ion occupying the gated cavity. Considerable water exchange occurs for the open-gate cavity when no ligand or cation is bound. In all cases, good correspondence is found between the calculated (ensemble-averaged) location of water molecules and the water sites determined by X-ray crystallography experiments. However, our simulations suggest that these sites do not necessarily correspond to the presence of bound water molecules. In fact, individual water molecules may repeatedly exchange within the cavity volume yet occupy on average these water sites. Four major conclusions emerge. First, it seems misleading to interpret the conformation of protein loop regions in terms of single dominant structures. Second, our simulations support the general picture of Pro 190 cis-trans isomerization as a determinant of the loop-opening mechanism. Third, receptor flexibility is fundamental for ligand binding and molecular recognition, and our results suggest its importance for the docking of small compounds to the artificial cavity. Fourth, after validation against the available experimental data, molecular dynamics simulations can be used to characterize the dynamics and exchange of water molecules and ions, providing atomic level and time-dependent information otherwise inaccessible to experiments.
机译：在明显的水中对细胞色素c过氧化物酶W191G腔突变体的五个分子动力学模拟显示出明显的动态和水合行为，具体取决于柔性环门控腔的闭合或开放状态，（K +或小分子）阳离子的结合以及系统温度。结合时环区域和腔所采样的构象空间显着减少。水动力学的最大排序因数是存在于门控腔中的K +离子的存在。当没有配体或阳离子结合时，对于开门腔会发生大量的水交换。在所有情况下，都可以在计算出的（整体平均）水分子位置与通过X射线晶体学实验确定的水位之间找到良好的对应关系。但是，我们的模拟表明这些位点不一定对应于结合水分子的存在。实际上，单个水分子可能会在型腔容积内反复交换，但平均占据这些水位。得出四个主要结论。首先，用单一显性结构解释蛋白质环区域的构象似乎具有误导性。第二，我们的模拟支持Pro 190顺反异构化作为开环机理的决定因素的总体情况。第三，受体的柔韧性是配体结合和分子识别的基础，我们的研究结果表明，受体的柔韧性对于小化合物对接至人工腔的重要性。第四，根据可用的实验数据进行验证后，分子动力学模拟可用于表征水分子和离子的动力学和交换，提供原子水平和时间相关的信息，而这些信息是实验无法获得的。

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