On the Dielectric "Constant" of Proteins: Smooth Dielectric Function for Macromolecular Modeling and Its Implementation in DelPhi.
On the Dielectric "Constant" of Proteins: Smooth Dielectric Function for Macromolecular Modeling and Its Implementation in DelPhi.
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DOI：
10.1021/ct400065j
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发表时间：
2013-04-09
影响因子：
5.5
通讯作者：
Alexov, Emil
中科院分区：
文献类型：
--
作者：
Li, Lin;Li, Chuan;Zhang, Zhe;Alexov, Emil
隐式蛋白质静电建模方法要求系统的介电特性是已知的，特别是蛋白质的介电常数。虽然文献中报道了许多蛋白质内部介电常数的值，但对于最佳值是什么仍然没有共识。也许这是因为蛋白质的介电常数不是一个“常数”，而是一个反映蛋白质结构和序列特性的复杂函数。在这里，我们报告了一种基于高斯的方法的实现，通过利用相应大分子的三维结构来传递整个蛋白质和周围水相的介电常数分布。与之前的报道相反，我们在整个待建模系统的空间中构建了一个平滑的介电函数，而不仅仅是构建一个“高斯表面”或平滑的分子-水边界。对大量蛋白质的分析表明：(a)蛋白质内部的平均介电常数相对较低，约为6-7，在蛋白质表面达到约20-30；(b)高平均局部介电常数值与带电残基相关，而低介电常数值自动分配给疏水残基所占据的区域。在能量学方面，对葡萄球菌核酸酶（SNase） 89个残基的实验pKa进行了基准测试，结果表明，它的RMSD （= 1.77 pK）比均匀高介电常数（最佳值为10）的相应计算要好得多（RMSD = 2.43 pK）。
Implicit methods for modeling protein electrostatics require dielectric properties of the system to be known, in particular, the value of the dielectric constant of protein. While numerous values of the internal protein dielectric constant were reported in the literature, still there is no consensus of what the optimal value is. Perhaps this is due to the fact that the protein dielectric constant is not a “constant” but is a complex function reflecting the properties of the protein’s structure and sequence. Here, we report an implementation of a Gaussian-based approach to deliver the dielectric constant distribution throughout the protein and surrounding water phase by utilizing the 3D structure of the corresponding macromolecule. In contrast to previous reports, we construct a smooth dielectric function throughout the space of the system to be modeled rather than just constructing a “Gaussian surface” or smoothing molecule–water boundary. Analysis on a large set of proteins shows that (a) the average dielectric constant inside the protein is relatively low, about 6–7, and reaches a value of about 20–30 at the protein’s surface, and (b) high average local dielectric constant values are associated with charged residues while low dielectric constant values are automatically assigned to the regions occupied by hydrophobic residues. In terms of energetics, a benchmarking test was carried out against the experimental pKa’s of 89 residues in staphylococcal nuclease (SNase) and showed that it results in a much better RMSD (= 1.77 pK) than the corresponding calculations done with a homogeneous high dielectric constant with an optimal value of 10 (RMSD = 2.43 pK).
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