Reliable Prediction of the Protein-Ligand Binding Affinity Using a Charge Penetration Corrected AMOEBA Force Field: A Case Study of Drug Resistance Mutations in Abl Kinase.

Protein mutations that directly impair drug binding are related to therapeutic resistance, and accurate prediction of their impact on drug binding would benefit drug design and clinical practice. Here, we have developed a scoring strategy that predicts the effect of the mutations on the protein-ligand binding affinity. In view of the critical importance of electrostatics in protein-ligand interactions, the charge penetration corrected AMOEBA force field (AMOEBA_CP model) was employed to improve the accuracy of the calculated electrostatic energy. We calculated the electrostatic energy using an energy decomposition analysis scheme based on the generalized Kohn-Sham (GKS-EDA). The AMOEBA_CP model was validated by a protein-fragment-ligand complex data set (Abl236) constructed from the co-crystal structures of the cancer target Abl kinase with six inhibitors. To predict ligand binding affinity changes upon protein mutation of Abl kinase, we used sampling protocol with multistep simulated annealing to search conformations of mutant proteins. The scoring strategy based on AMOEBA_CP model has achieved considerable performance in predicting resistance for 8 kinase inhibitors across 144 clinically identified point mutations. Overall, this study illustrates that the AMOEBA_CP model, which accurately treats electrostatics through penetration correction, enables the accurate prediction of the mutation-induced variation of protein-ligand binding affinity.