论文标题
使用集合表示在化学复合空间中自由能的机器学习:达到溶剂化的实验不确定性
Machine Learning of Free Energies in Chemical Compound Space Using Ensemble Representations: Reaching Experimental Uncertainty for Solvation
论文作者
论文摘要
自由能控制软液体和液体物质的行为,改善其预测可能会对药物,电解质或均质催化剂的发展产生很大的影响。不幸的是,精确地描述了有关溶剂化的效果的准确描述,例如氢键,范德华相互作用或构象采样,这是一项挑战。我们提出了适用于整个化学复合空间的自由能机学习(FML)模型,并基于采用Boltzmann平均值来说明配置空间的近似采样的表示形式。使用FREESOLV数据库,在训练490分子(80 \%freeesolv的80 \%)训练后,可以系统地衰减FML的实验水合自由能的样本外预测误差,并在训练集大小(0.6 kcal/mol)中系统地衰减(0.6 kcal/mol)。相应的FML模型错误也与基于最新物理的方法相提并论。为了生成新查询化合物的输入表示形式,FML需要运行近似和短分子动力学。我们通过分析116K有机分子的FML溶剂化自由能(QM9数据库中的所有力场兼容分子)来展示其有用性原子。当用于生成训练中的平均输入表示样品的分子动力学模拟的温度与查询化合物相同时,FML的精度是最大的。相对于预测误差,表示表示时间迅速收敛。
Free energies govern the behavior of soft and liquid matter, and improving their predictions could have a large impact on the development of drugs, electrolytes or homogeneous catalysts. Unfortunately, it is challenging to devise an accurate description of effects governing solvation such as hydrogen-bonding, van der Waals interactions, or conformational sampling. We present a Free energy Machine Learning (FML) model applicable throughout chemical compound space and based on a representation that employs Boltzmann averages to account for an approximated sampling of configurational space. Using the FreeSolv database, FML's out-of-sample prediction errors of experimental hydration free energies decay systematically with training set size, and experimental uncertainty (0.6 kcal/mol) is reached after training on 490 molecules (80\% of FreeSolv). Corresponding FML model errors are also on par with state-of-the art physics based approaches. To generate the input representation for a new query compound, FML requires approximate and short molecular dynamics runs. We showcase its usefulness through analysis of FML solvation free energies for 116k organic molecules (all force-field compatible molecules in QM9 database) identifying the most and least solvated systems, and rediscovering quasi-linear structure property relationships in terms of simple descriptors such as hydrogen-bond donors, number of NH or OH groups, number of oxygen atoms in hydrocarbons, and number of heavy atoms. FML's accuracy is maximal when the temperature used for the molecular dynamics simulation to generate averaged input representation samples in training is the same as for the query compounds. The sampling time for the representation converges rapidly with respect to the prediction error.