Computations of standard binding free energies with molecular dynamics simulations.
Computations of standard binding free energies with molecular dynamics simulations.
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DOI：
10.1021/jp807701h
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发表时间：
2009-02-26
期刊：
影响因子：
--
通讯作者：
Roux B
中科院分区：
文献类型：
--
作者：
Deng Y;Roux B
越来越多的研究报道了利用分子动力学（MD）模拟计算小配体与蛋白质的绝对结合自由能，其结果与实验结果很好地吻合。这一令人鼓舞的进展表明，基于物理的方法有望在不久的将来为药物发现和优化过程做出重要贡献。两种方法主要用于计算结合自由能与MD模拟。最广为人知的是基于炼金术的自由能方法，在这种方法中，配体与其周围的相互作用逐渐被切断。另一种方法是使用平均力势（PMF），其中配体与蛋白质受体物理分离。对于这两种计算方法，影响配体和蛋白质的平移、旋转和构象自由的抑制电位可能在模拟过程中被激活和释放，以帮助收敛和改善采样。这样的抑制势会给模拟增加偏置，但它们的影响可以被严格地去除，从而产生一个相对于标准状态适当无偏置的结合自由能。对最近的结果进行了回顾。讨论并比较了t4溶菌酶突变体、FKBP12、SH2结构域和细胞色素P450的计算实例。讨论了计算方法的差异，并强调了仍然存在的困难和挑战。
An increasing number of studies have reported computations of the absolute binding free energy of small ligands to proteins using molecular dynamics (MD) simulations with results that are in good agreement with experiments. This encouraging progress suggests that physics-based approaches hold the promise of making important contributions to the process of drug discovery and optimization in the near future. Two types of approaches are principally used to compute binding free energies with MD simulations. The most widely known are based on alchemical free energy methods, in which the interaction of the ligand with its surrounding are progressively switched off. An alternative method is to use a potential of mean force (PMF), in which the ligand is physically separated from the protein receptor. For both of these computational approaches, restraining potentials affecting the translational, rotational and conformational freedom of the ligand and protein may be activated and released during the simulations to aid convergence and improve the sampling. Such restraining potentials add bias to the simulations, but their effects can be rigorously removed to yield a binding free energy that is properly unbiased with respect to the standard state. A review of recent results is presented. Examples of computations with T4-lysozyme mutants, FKBP12, SH2 domain, and cytochrome P450 are discussed and compared. Differences in computational methods are discussed and remaining difficulties and challenges are highlighted.
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DOI：
10.1073/pnas.1037393100
发表时间：
2003-05-13
影响因子：
11.1
作者：
Armstrong, N;Mayer, M;Gouaux, E
通讯作者：
Gouaux, E
影响因子：
4.4
作者：
BEUTLER, TC;VANGUNSTEREN, WF
通讯作者：
VANGUNSTEREN, WF
影响因子：
3.3
作者：
Boresch, S;Tettinger, F;Karplus, M
通讯作者：
Karplus, M
影响因子：
4.4
作者：
BEGLOV, D;ROUX, B
通讯作者：
ROUX, B
影响因子：
5.5
作者：
Deng, Yuqing;Roux, Benoit
通讯作者：
Roux, Benoit