Capturing the energetics of water insertion in biological systems: the water flooding approach.
Capturing the energetics of water insertion in biological systems: the water flooding approach.
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DOI：
10.1002/prot.24165
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发表时间：
2013-01
期刊：
影响因子：
2.9
通讯作者：
Warshel A
中科院分区：
文献类型：
--
作者：
Chakrabarty S;Warshel A
对蛋白质内部水的作用进行一致的描述一直是模拟和实验研究的重大挑战。在蛋白质内部存在电荷的情况下，这种作用尤为重要且难以捉摸。在此我们提出一种新的微观方法，为模拟水插入的能量学提供了一种有效的途径。我们的方法不是对插入过程进行显式的蒙特卡罗（MC）移动（这通常涉及大量被拒绝的尝试），而是基于生成含有过量内部水的尝试构型，通过线性响应近似（LRA）估计相关自由能，然后使用后处理的蒙特卡罗处理从大量可能的集合中筛选出有限数量的构型。我们的方法在特别具有挑战性的测试案例上得到了验证，包括金黄色葡萄球菌核酸酶（SNase）中V66D突变的pKa值、细胞色素c氧化酶（CcO）中的Glu286以及CcO的D通道中一个质子化水分子的能量学。这种方法使我们能够使用完全微观的计算重现蛋白质内部高度不稳定电荷的相关能量学，并相对于常规微观自由能估计有非常显著的改进。这确立了我们的水插入策略在其他微观方法未能成功解决的具有挑战性的情况下的有效性。此外，我们的研究为水在关键生物系统中的渗透这一关键作用提供了一种令人兴奋的新视角，以及对蛋白质内部介电性质的新视角。
Consistent description of the effect of internal water in proteins has been a major challenge for both simulation and experimental studies. This effect has been particularly important and elusive in cases of charges in protein interiors. Here we present a new microscopic method that provides an efficient way for simulating the energetics of water insertion. Instead of performing explicit Monte Carlo (MC) moves on the insertion process, which generally involves an enormous number of rejected attempts, our method is based on generating trial configurations with excess amount of internal water, estimating the relevant free energy by the linear response approximation (LRA) and then using a postprocessing MC treatment to filter out a limited number of configurations from a very large possible set. Our approach is validated on particularly challenging test cases including the pKa of the V66D mutation in Staphylococcal Nuclease (SNase), Glu286 in Cytochrome c Oxidase (CcO) and the energetics of a protonated water molecule in the D channel of CcO. This approach allows us to reproduce the relevant energetics of highly unstable charges in protein interiors using fully microscopic calculations and provides a very substantial improvement over regular microscopic free energy estimates. This establishes the effectiveness of our water insertion strategy in challenging cases that have not been addressed successfully by other microscopic methods. Furthermore, our study provides a new exciting view on the crucial effect of water penetration in key biological systems as well as a new view on the nature of the dielectric in protein interiors.