Force Field Optimization Guided by Small Molecule Crystal Lattice Data Enables Consistent Sub-Angstrom Protein-Ligand Docking.
Force Field Optimization Guided by Small Molecule Crystal Lattice Data Enables Consistent Sub-Angstrom Protein-Ligand Docking.
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由小分子晶格数据引导的力场优化可以使一致的子角蛋白蛋白质配体对接。
DOI：
10.1021/acs.jctc.0c01184
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发表时间：
2021-03-09
影响因子：
5.5
通讯作者：
DiMaio F
中科院分区：
文献类型：
--
作者：
Park H;Zhou G;Baek M;Baker D;DiMaio F
准确、快速地计算蛋白质与小分子相互作用的自由能对于计算药物的发现至关重要。由于类药物分子所跨越的化学空间很大，经典力场包含数千个描述原子对距离和扭转偏好的参数；每个参数通常在简单的代表性分子上独立优化。本文描述了一种利用数千个可用小分子晶体结构中包含的丰富信息源来共同优化小分子力场参数的新方法。我们通过要求实验确定的分子晶格排列比所有其他晶格排列具有更低的能量来优化参数。对1386种小分子晶体结构分别进行了数千次独立的晶格预测模拟，优化了隐式溶剂能量模型的能量函数参数，使天然晶格排列具有最低的能量。在Rosetta中实现了生成的能量模型，并结合基于网格评分和受体灵活性的快速遗传算法对接方法。在1112个配合物的交叉对接中，结合结构再现的成功率比先前发表的方法提高了10%以上，在超过一半的情况下，解在<1 Å范围内。我们的研究结果表明，小分子晶体结构是指导分子力场发展的丰富信息来源，改进的Rosetta能量函数将提高小分子结构预测和设计研究的准确性。
Accurate and rapid calculation of protein-small molecule interaction free energies is critical for computational drug discovery. Because of the large chemical space spanned by drug-like molecules, classical force fields contain thousands of parameters describing atom-pair distance and torsional preferences; each parameter is typically optimized independently on simple representative molecules. Here we describe a new approach in which small molecule force field parameters are jointly optimized guided by the rich source of information contained within thousands of available small molecule crystal structures. We optimize parameters by requiring that the experimentally determined molecular lattice arrangements have lower energy than all alternative lattice arrangements. Thousands of independent crystal lattice-prediction simulations were run on each of 1,386 small molecule crystal structures, and energy function parameters of an implicit solvent energy model were optimized so native crystal lattice arrangements had the lowest energy. The resulting energy model was implemented in Rosetta, together with a rapid genetic algorithm docking method employing grid-based scoring and receptor flexibility. The success rate of bound structure recapitulation in cross-docking on 1,112 complexes was improved by more than 10% over previously published methods, with solutions within <1 Å in over half of the cases. Our results demonstrate that small molecule crystal structures are a rich source of information for guiding molecular force field development, and the improved Rosetta energy function should increase accuracy in a wide range of small molecule structure prediction and design studies.
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DOI：
10.1107/s2052520616006831
发表时间：
2016-08-01
影响因子：
1.9
作者：
Broo, Anders;Lill, Sten O. Nilsson
通讯作者：
Lill, Sten O. Nilsson
影响因子：
4.4
作者：
JORGENSEN, WL;CHANDRASEKHAR, J;KLEIN, ML
通讯作者：
KLEIN, ML
影响因子：
62.1
作者：
Lemkul JA;Huang J;Roux B;MacKerell AD Jr
通讯作者：
MacKerell AD Jr
影响因子：
5.5
作者：
Boulanger, Eliot;Huang, Lei;Roux, Benoit
通讯作者：
Roux, Benoit
影响因子：
5.5
作者：
Alford, Rebecca F.;Leaver-Fay, Andrew;Gray, Jeffrey J.
通讯作者：
Gray, Jeffrey J.