Computer simulation of protein-protein association kinetics: Acetylcholinesterase-fasciculin
Computer simulation of protein-protein association kinetics: Acetylcholinesterase-fasciculin
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DOI：
10.1006/jmbi.1999.2919
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发表时间：
1999-08-06
影响因子：
5.6
通讯作者：
McCammon, JA
中科院分区：
文献类型：
--
作者：
Elcock, AH;Gabdoulline, RR;McCammon, JA
通过计算机模拟研究了静电相互作用在促进乙酰胆碱酯酶与其肽抑制剂神经毒素fasciculin快速结合中的作用。的两个大分子的遭遇与布朗动力学（BD）的技术进行了模拟，使用原子详细的结构，并计算了野生型和一些突变蛋白的缔合速率常数。在第一组模拟中，突变蛋白质的实验速率常数的顺序被正确地再现，尽管速率常数的绝对值被高估了约30倍。两种蛋白质之间的完整静电相互作用能的严格计算表明，这种高估的关联率的结果至少部分地从近似的相互作用能量的描述中的艾德模拟。特别是，最初的艾德模拟忽略了不利的静电去溶剂化的影响，导致从排除高介电溶剂，伴随着两个低介电蛋白质的方法。这种静电去溶剂化组分是如此之大，以至于静电对络合物的结合能的总体贡献不太可能是强烈有利的。然而，静电相互作用仍然是增加缔合速率的原因，因为即使它们在完全形成的复合物中是不利的，它们在中间蛋白质-蛋白质分离距离处仍然是有利的。因此，静电相互作用似乎有可能促进结合的动力学，即使它们对结合的热力学没有强烈的有利贡献。当这些静电去溶剂化效应的近似描述包括在第二组艾德模拟中时，突变蛋白的相对排序再次正确地再现，但是现在获得的缔合速率常数在幅度上更接近实验值。静电去溶剂化效应的列入也提高了野生型缔合速率的实验离子强度依赖性的再现。(C)北京：科学出版社.
Computer simulations were performed to investigate the role of electrostatic interactions in promoting fast association of acetylcholinesterase with its peptidic inhibitor, the neurotoxin fasciculin. The encounter of the two macromolecules was simulated with the technique of Brownian dynamics (BD), using atomically detailed structures, and association rate constants were calculated for the wild-type and a number of mutant proteins. In a first set of simulations, the ordering of the experimental rate constants for the mutant proteins was correctly reproduced, although the absolute values of the rate constants were overestimated by a factor of around 30. Rigorous calculations of the full electrostatic interaction energy between the two proteins indicate that this overestimation of association rates results at least in part from approximations made in the description of interaction energetics in the ED simulations. In particular, the initial ED simulations neglect the unfavourable electrostatic desolvation effects that result from the exclusion of high dielectric solvent that accompanies the approach of the two low dielectric proteins. This electrostatic desolvation component is so large that the overall contribution of electrostatics to the binding energy of the complex is unlikely to be strongly favourable. Nevertheless, electrostatic interactions are still responsible for increased association rates, because even if they are unfavourable in the fully formed complex, they are still favourable at intermediate protein-protein separation distances. It therefore appears possible for electrostatic interactions to promote the kinetics of binding even if they do not make a strongly favourable contribution to the thermodynamics of binding. When an approximate description of these electrostatic desolvation effects is included in a second set of ED simulations, the relative ordering of the mutant proteins is again correctly reproduced, but now association rate constants that are much closer in magnitude to the experimental values are obtained. Inclusion of electrostatic desolvation effects also improves reproduction of the experimental ionic strength dependence of the wild-type association rate. (C) 1999 Academic Press.