Water in the polar and nonpolar cavities of the protein interleukin-1β.
Water in the polar and nonpolar cavities of the protein interleukin-1β.
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DOI：
10.1021/jp108731r
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发表时间：
2010-12-16
影响因子：
3.3
通讯作者：
Rasaiah, Jayendran C.
中科院分区：
文献类型：
--
作者：
Yin, Hao;Feng, Guogang;Clore, G. Marius;Hummer, Gerhard;Rasaiah, Jayendran C.
蛋白质内部的水具有重要的结构和功能作用，并且也越来越多地被认为是药物结合的相关因素。据报道，基于一些实验和模拟，蛋白质白细胞介素-1 β中的非极性空腔被水填充，而基于其他实验和模拟，非极性空腔是空的。本文采用分子动力学模拟方法研究了白细胞介素1β填充中心非极性空穴和四个极性空穴的热力学过程。我们使用不同的水模型（TIP 3 P和SPC/E）和蛋白质力场（amber 94和amber 03）来计算量化水合平衡的半巨配分函数。我们一致地发现，中心非极性腔中水是不稳定的，与力场和水模型无关。表面上的原因是相对较小的空腔尺寸，体积小于1080立方厘米。我们的研究结果与最新的X射线晶体学和模拟研究相一致，但不同意早期的核磁共振（NMR）实验探测蛋白质-水相互作用的解释。我们表明，至少半定量地，测得的核Overhauser效应表明接近水的甲基内衬的非极性腔，在所有的可能性，是由于相互作用与埋在地下和地表水分子附近的腔。用于确定极性腔的占有率的相同方法表明，它们被晶体学中观察到的相同数量的水分子填充，从而验证了用于研究非极性蛋白质腔中的水占有率的理论和模拟方法。
Water in the protein interior serves important structural and functional roles, and is also increasingly recognized as a relevant factor in drug binding. The nonpolar cavity in the protein interleukin-1β has been reported to be filled by water based on some experiments and simulations, and to be empty based on others. Here we study the thermodynamics of filling the central nonpolar cavity and the four polar cavities of interleukin-1β by molecular dynamics simulation. We use different water models (TIP3P and SPC/E) and protein force fields (amber94 and amber03) to calculate the semi-grand partition functions term by term that quantify the hydration equilibria. We consistently find that water in the central nonpolar cavity is thermodynamically unstable, independent of force field and water model. The apparent reason is the relatively small size of the cavity, with a volume less than ∼80 Å3. Our results are consistent with the most recent X-ray crystallographic and simulation studies, but disagree with an earlier interpretation of nuclear magnetic resonance (NMR) experiments probing protein-water interactions. We show that, at least semi-quantitatively, the measured nuclear Overhauser effects indicating the proximity of water to the methyl groups lining the nonpolar cavity can, in all likelihood, be attributed to interactions with buried and surface water molecules near the cavity. The same methods applied to determine the occupancy of the polar cavities show that they are filled by the same number of water molecules observed in crystallography, thereby validating the theoretical and simulation methods used to study the water occupancy in the nonpolar protein cavity.
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影响因子：
4.1
作者：
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通讯作者：
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作者：
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