QupKake: Integrating Machine Learning and Quantum Chemistry for Micro-pKa Predictions.

Abstract

Accurate prediction of micro-pKa values is crucial for understanding and modulating the acidity and basicity of organic molecules, with applications in drug discovery, materials science, and environmental chemistry. This work introduces QupKake, a novel method that combines graph neural network models with semiempirical quantum mechanical (QM) features to achieve exceptional accuracy and generalization in micro-pKa prediction. QupKake outperforms state-of-the-art models on a variety of benchmark data sets, with root-mean-square errors between 0.5 and 0.8 pKa units on five external test sets. Feature importance analysis reveals the crucial role of QM features in both the reaction site enumeration and micro-pKa prediction models. QupKake represents a significant advancement in micro-pKa prediction, offering a powerful tool for various applications in chemistry and beyond.