Protein pK _a Prediction with Machine Learning

Protein pK _a prediction is essential for the investigation of the pH-associated relationship between protein structure and function. In this work, we introduce a deep learning-based protein pK _a predictor DeepKa, which is trained and validated with the pK _a values derived from continuous constant-pH molecular dynamics (CpHMD) simulations of 279 soluble proteins. Here, the CpHMD implemented in the Amber molecular dynamics package has been employed (Huang Y.J. Chem. Inf. Model.2018, 58, 1372-1383). Notably, to avoid discontinuities at the boundary, grid charges are proposed to represent protein electrostatics. We show that the prediction accuracy by DeepKa is close to that by CpHMD benchmarking simulations, validating DeepKa as an efficient protein pK _a predictor. In addition, the training and validation sets created in this study can be applied to the development of machine learning-based protein pK _a predictors in the future. Finally, the grid charge representation is general and applicable to other topics, such as the protein-ligand binding affinity prediction.