Multidimensional Global Optimization and Robustness Analysis in the Context of Protein-Ligand Binding.
Multidimensional Global Optimization and Robustness Analysis in the Context of Protein-Ligand Binding.
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DOI：
10.1021/acs.jctc.0c00142
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发表时间：
2020-07-14
影响因子：
5.5
通讯作者：
Onufriev AV
中科院分区：
文献类型：
--
作者：
Forouzesh N;Mukhopadhyay A;Watson LT;Onufriev AV
利用隐式溶剂模型的蛋白质-配体结合自由能计算的准确性受到底层介电边界的参数的严重影响，特别是原子和水探针半径。在这里，开发了一个全局多维优化管道，以找到最佳的原子半径，特别是在隐式溶剂中的蛋白质-配体结合计算。计算流水线具有以下三个关键组成部分：（1）确定性全局优化算法（VTDIRECT 95）的大规模并行实现，（2）准确但相当快速的广义Born隐式溶剂模型（GBNSR 6），以及（3）新的鲁棒性度量，有助于通过优化的后处理步骤区分几乎退化的局部最小值。提出了一种基于图的“kT-连通性”方法来探索和可视化多维能量景观：可以从全局最小值到达而不超过给定能量阈值（kT）的局部最小值被认为是连通的。作为优化管道功能的一个例子，我们将其应用于在只有五个半径的空间中找到全局最优值：四个原子（O，H，N和C）半径和水探针半径。优化半径，ρW = 1.37 <$，ρC = 1.40 <$，ρH = 1.55 <$，ρN = 2.35 <$和ρO = 1.28 <$，导致静电结合自由能与显式溶剂参考比两组常用的半径先前优化的小分子更接近。与此同时，优化器找到全局最优值的能力揭示了常见的2-介电隐式溶剂化模型的基本限制：计算的静电结合自由能仍然几乎4千卡/摩尔远离显式溶剂参考。所提出的计算方法打开了进一步提高结合自由能计算的实际计算协议的准确性的可能性。
Accuracy of protein-ligand binding free energy calculations utilizing implicit solvent models is critically affected by parameters of the underlying dielectric boundary, specifically the atomic and water probe radii. Here, a global multidimensional optimization pipeline is developed to find optimal atomic radii specifically for protein-ligand binding calculations in implicit solvent. The computational pipeline has these three key components: (1) a massively parallel implementation of a deterministic global optimization algorithm (VTDIRECT95), (2) an accurate yet reasonably fast generalized Born implicit solvent model (GBNSR6), and (3) a novel robustness metric that helps distinguish between nearly degenerate local minima via a post-processing step of the optimization. A graph-based “kT-connectivity” approach to explore and visualize the multidimensional energy landscape is proposed: local minima that can be reached from the global minimum without exceeding a given energy threshold (kT) are considered connected. As an illustration of the capabilities of the optimization pipeline, we apply it to find a global optimum in the space of just five radii: four atomic (O, H, N, and C) radii and water probe radius. The optimized radii, ρW = 1.37 Å, ρC = 1.40 Å, ρH = 1.55 Å, ρN = 2.35 Å and ρO = 1.28 Å, lead to a closer agreement of electrostatic binding free energies with the explicit solvent reference than two commonly used sets of radii previously optimized for small molecules. At the same time, the ability of the optimizer to find the global optimum reveals fundamental limits of the common 2-dielectric implicit solvation model: the computed electrostatic binding free energies are still almost 4 kcal/mol away from the explicit solvent reference. The proposed computational approach opens the possibility to further improve the accuracy of practical computational protocols for binding free energy calculations.
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影响因子：
5.5
作者：
Aguilar, Boris;Shadrach, Richard;Onufriev, Alexey V.
通讯作者：
Onufriev, Alexey V.
影响因子：
2.9
作者：
BASHFORD, D;KARPLUS, M
通讯作者：
KARPLUS, M
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：
3
作者：
Chen, Duan;Chen, Zhan;Chen, Changjun;Geng, Weihua;Wei, Guo-Wei
通讯作者：
Wei, Guo-Wei
影响因子：
3.3
作者：
Dominy, BN;Brooks, CL
通讯作者：
Brooks, CL