Alchemical Free Energy Estimators and Molecular Dynamics Engines: Accuracy, Precision, and Reproducibility.
Alchemical Free Energy Estimators and Molecular Dynamics Engines: Accuracy, Precision, and Reproducibility.
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炼金术自由能估计器和分子动力学引擎：准确性，精度和可重复性。
DOI：
10.1021/acs.jctc.2c00114
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发表时间：
2022-06-14
影响因子：
5.5
通讯作者：
Coveney, Peter, V
中科院分区：
文献类型：
--
作者：
Wade, Alexander D.;Bhati, Agastya P.;Wan, Shunzhou;Coveney, Peter, V
配体与其靶蛋白之间的结合自由能是药物发现流程各个阶段需要了解的重要量。通过计算评估这个值可以深入了解在寻求有效的治疗方法来治疗多种疾病时应将努力的重点放在哪里。在这项工作中，我们研究了炼金术相对结合自由能的计算，着眼于评估流行的分子动力学包和自由能估计器的再现性。这项工作的重点是来自一组不同蛋白质靶标的 54 个配体转化：MCL1、PTP1B、TYK2、CDK2 和凝血酶。这些目标通过三种流行的分子动力学软件包进行研究：OpenMM、NAMD2 和 NAMD3 alpha。使用这些包收集的轨迹用于比较通过热力学积分和自由能扰动方法计算的相对结合自由能。所得的结合自由能显示分子动力学包之间具有良好的一致性，它们之间的平均无符号误差为 0.50 kcal/mol。包之间的相关性非常好，Spearman’s、Pearson’s 和 Kendall’s tau 相关系数最低，分别为 0.92、0.91 和 0.76。当使用系综平均时，热力学积分和自由能扰动之间的一致性非常好。
The binding free energy between a ligand and its target protein is an essential quantity to know at all stages of the drug discovery pipeline. Assessing this value computationally can offer insight into where efforts should be focused in the pursuit of effective therapeutics to treat a myriad of diseases. In this work, we examine the computation of alchemical relative binding free energies with an eye for assessing reproducibility across popular molecular dynamics packages and free energy estimators. The focus of this work is on 54 ligand transformations from a diverse set of protein targets: MCL1, PTP1B, TYK2, CDK2, and thrombin. These targets are studied with three popular molecular dynamics packages: OpenMM, NAMD2, and NAMD3 alpha. Trajectories collected with these packages are used to compare relative binding free energies calculated with thermodynamic integration and free energy perturbation methods. The resulting binding free energies show good agreement between molecular dynamics packages with an average mean unsigned error between them of 0.50 kcal/mol. The correlation between packages is very good, with the lowest Spearman’s, Pearson’s and Kendall’s tau correlation coefficients being 0.92, 0.91, and 0.76, respectively. Agreement between thermodynamic integration and free energy perturbation is shown to be very good when using ensemble averaging.
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影响因子：
3.6
作者：
Blaschke T;Olivecrona M;Engkvist O;Bajorath J;Chen H
通讯作者：
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影响因子：
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作者：
Klimovich, Pavel V.;Shirts, Michael R.;Mobley, David L.
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通讯作者：
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影响因子：
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作者：
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