DFT-Machine Learning Approach for Accurate Prediction of pKa

In this study, we propose a novel method of pK_a prediction in a diverse set of acids, which combines density functional theory (DFT) method with machine learning (ML) methods. First, the DFT method with B3LYP/6-31++G**/SM8 is used to predict pK_a, yielding a mean absolute error of 1.85 pK_a units. Subsequently, such pK_a values predicted from the DFT method are employed as one of 10 molecular descriptors for developing ML models trained on experimental data. Kernel Ridge Regression (KRR), Gaussian Process Regression, and Artificial Neural Network are optimized using three Pipelines: Pipeline 1 involving only hyperparameter optimization (HPO), Pipeline 2 involving HPO followed by a relative contribution analysis (RCA) and recursive feature elimination (RFE), and Pipeline 3 involving HPO followed by RCA and RFE on an expanded set of composite features. Finally, it is demonstrated that KRR with Pipeline 3 yields optimal pK_a prediction at an MAE of 0.60 log units. This algorithm was then utilized to predict the pK_a of 37 novel acids. The two most important features were determined to be the number of hydrogen atoms in the molecule and the degree of oxidation of the acid. The predicted pK_a values were documented for future reference.