Standard binding free energies from computer simulations: What is the best strategy?
Standard binding free energies from computer simulations: What is the best strategy?
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DOI：
10.1021/ct3008099
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发表时间：
2013-01-08
影响因子：
5.5
通讯作者：
Chipot, Christophe
中科院分区：
文献类型：
--
作者：
Gumbart, James C.;Roux, Benoit;Chipot, Christophe
准确预测描述蛋白质配体结合的标准结合自由能仍然是一项艰巨的计算工作。这一挑战在很大程度上源于结合过程中构象、平动和旋转熵的巨大变化，而原子模拟不容易捕捉到这些变化。尽管在方法上取得了重大进展，这反映在与实验的一致性不断提高上，但对旨在测量结合亲和力的替代策略的特征描述，特别是它们各自的优点和缺点，在某种程度上是缺乏的。本文比较了与酪氨酸激酶Abl的Src同源结构域3相关的富含脯氨酸的短肽确定标准结合自由能的两种不同途径。这些途径——一个依赖于炼金术转化，另一个依赖于平均力势（PMFs）——调用了一系列的几何约束，这些约束作用于集体变量，旨在减轻经典分子动力学模拟固有的采样限制。本文所建立的两种策略可以很好地再现实验的结合自由能ΔGbind =−7.99 kcal/mol，炼金术路线的结合自由能ΔGbind =−7.7，替代pmf路线的结合自由能ΔGbind =−7.8 kcal/mol。在详细介绍这些为精确确定标准束缚自由能而设计的数值策略的基础时，阐明了所提出的严格的概念框架的许多实际元素，从而为解决几乎任何识别和关联现象铺平了道路。
Accurate prediction of standard binding free energies describing protein:ligand association remains a daunting computational endeavor. This challenge is rooted to a large extent in the considerable changes in conformational, translational and rotational entropies underlying the binding process that atomistic simulations cannot easily capture. In spite of significant methodological advances, reflected in a continuously improving agreement with experiment, a characterization of alternate strategies aimed at measuring binding affinities, notably their respective advantages and drawbacks, is somewhat lacking. Here, two distinct avenues to determine the standard binding free energy are compared in the case of a short, proline-rich peptide associating to the Src homology domain 3 of tyrosine kinase Abl. These avenues – one relying upon alchemical transformations and the other on potentials of mean force (PMFs) – invoke a series of geometrical restraints acting on collective variables designed to alleviate sampling limitations inherent to classical molecular dynamics simulations. The experimental binding free energy of ΔGbind = −7.99 kcal/mol is well reproduced by the two strategies developed herein, with ΔGbind = −7.7 for the alchemical route and ΔGbind = −7.8 kcal/mol for the alternate PMF-based route. In detailing the underpinnings of these numerical strategies devised for the accurate determination of standard binding free energies, many practical elements of the proposed rigorous, conceptual framework are clarified, thereby paving way to tackle virtually any recognition and association phenomenon.
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影响因子：
4.1
作者：
BENNETT, CH
通讯作者：
BENNETT, CH
影响因子：
2.8
作者：
BEUTLER, TC;MARK, AE;VANGUNSTEREN, WF
通讯作者：
VANGUNSTEREN, WF
DOI：
10.1021/jp807701h
发表时间：
2009-02-26
期刊：
The journal of physical chemistry. B
影响因子：
--
作者：
Deng Y;Roux B
通讯作者：
Roux B
影响因子：
5.5
作者：
Best, Robert B.;Zhu, Xiao;Shim, Jihyun;Lopes, Pedro E. M.;Mittal, Jeetain;Feig, Michael;MacKerell, Alexander D., Jr.
通讯作者：
MacKerell, Alexander D., Jr.
影响因子：
4.4
作者：
FELLER, SE;ZHANG, YH;BROOKS, BR
通讯作者：
BROOKS, BR