Theoretical calculation of protein-protein and protein-ligand binding free energies is a grand challenge in computational biology. Accurate prediction of critical residues along with their specific and quantitative contributions to protein-protein binding free energy is extremely helpful to reveal binding mechanisms and identify drug-like molecules that alter protein-protein interactions. In this talk we develop an efficient approach (Interaction Entropy) to computing quantitative residue-specific contributions to protein-protein and protein-ligand binding free energies. The approach provides explicit contribution of the entropic loss in binding free energy of individual residues directly from fluctuation of the interaction energy in MD simulation. Studies for an extensive set of realistic protein-protein interaction systems and for specific protein-ligand binding systems showed that by including the entropic contribution, the computed residue-specific binding free energies are in better agreement with the corresponding experimental data. Predictions of hot stops for some important protein-protein interactions are discussed.

References

1. Duan, L.L., X. Liu, and J.Z.H. Zhang, Interaction Entropy: A New Paradigm for Highly Efficient and Reliable Computation of Protein-Ligand Binding Free Energy. J. Am. Chem. Soc., 2016. 138(17): p. 5722-5728.
2. Sun, Z.; Yan, Y.; Yang, M.; Zhang, J.Z.H., Interaction entropy for protein-protein binding. J. Chem. Phys., 2017. 146, 124124.
3. Yan, Y.; Yang, M.; Ji, C.; Zhang, J.Z.H., Interaction Entropy for Computational Alanine Scanning. J. Chem. Inf. Model., 2017. 57, 1112–1122.
4. Liu, X.; Peng, L.; Zhou, Y.; Zhang, Y.; Zhang, J.Z.H.; Computational Alanine Scanning with Interaction Entropy for Protein–Ligand Binding Free Energies, J. Chem. Theo. Comput., 2018, 14 (3), 1772–1780.