Optimized Lennard-Jones Parameters for Druglike Small Molecules
Optimized Lennard-Jones Parameters for Druglike Small Molecules
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DOI：
10.1021/acs.jctc.8b00172
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发表时间：
2018-06-01
影响因子：
5.5
通讯作者：
Roux, Benoit
中科院分区：
文献类型：
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作者：
Boulanger, Eliot;Huang, Lei;Roux, Benoit
计算机辅助药物设计（CADD）中有意义的努力需要准确的分子机械力场来定量表征蛋白质-配体相互作用、配体水合自由能和其他配体物理性质。新化合物的原子模型通常通过从给定力场的预定义列表参数进行类比来生成。在这一战略之后，两种广泛使用的方法是琥珀一般力场（GAFF）和CHARMM一般力场（CGenFF）。使用预先列表的参数值的一个重要限制是它们在特定分子的情况下可能是不充分的。为了解决这个问题，我们以前介绍了通用自动原子模型参数化（GAAMP），用于自动生成小分子原子模型的参数，使用从头计算量子力学（QM）计算的结果作为目标数据。GAAMP协议使用QM数据来优化键、价角和二面角内部参数以及原子部分电荷。然而，由于基于QM的货车范德华相互作用的处理是具有挑战性的，并且通常可能是不可靠的，因此Lennard-Jones 6-12参数与初始原子类型分配（GAFF或CGenFF）保持不变，这限制了这些模型可以实现的准确性。为了解决这个问题，一组新的Lennard-Jones 6-12参数进行了系统优化，以重现实验纯液体密度和蒸发的一个大的集合的430种化合物，涵盖了广泛的化学功能。水化自由能的计算表明，这些模型的最佳精度时，达到分子-水货车的德瓦尔斯分散体是由1.115的一个因素重新缩放。最终优化的模型产生的平均无符号误差为0.79千卡/摩尔的水合自由能。
Meaningful efforts in computer-aided drug design (CADD) require accurate molecular mechanical force fields to quantitatively characterize protein-ligand interactions, ligand hydration free energies, and other ligand physical properties. Atomic models of new compounds are commonly generated by analogy from the predefined tabulated parameters of a given force field. Two widely used approaches following this strategy are the General Amber Force Field (GAFF) and the CHARMM General Force Field (CGenFF). An important limitation of using pretabulated parameter values is that they may be inadequate in the context of a specific molecule. To resolve this issue, we previously introduced the General Automated Atomic Model Parameterization (GAAMP) for automatically generating the parameters of atomic models of small molecules, using the results from ab initio quantum mechanical (QM) calculations as target data. The GAAMP protocol uses QM data to optimize the bond, valence angle, and dihedral angle internal parameters, and atomic partial charges. However, since the treatment of van der Waals interactions based on QM is challenging and may often be unreliable, the Lennard-Jones 6-12 parameters are kept unchanged from the initial atom types assignments (GAFF or CGenFF), which limits the accuracy that can be achieved by these models. To address this issue, a new set of Lennard-Jones 6-12 parameters was systematically optimized to reproduce experimental neat liquid densities and enthalpies of vaporization for a large set of 430 compounds, covering a wide range of chemical functionalities. Calculations of the hydration free energy indicate that optimal accuracy for these models is achieved when the molecule-water van der Waals dispersion is rescaled by a factor of 1.115. The final optimized model yields an average unsigned error of 0.79 kcal/mol in the hydration free energies.