Improving the Performance of MM/PBSA in Protein-Protein Interactions via the Screening Electrostatic Energy

Accurate calculation of protein-protein binding free energy is of great importance in biological and medical science, yet it remains a hugely challenging problem. In this work, we develop a new strategy in which a screened electrostatic energy (i.e., adding an exponential damping factor to the Coulombic interaction energy) is used within the framework of the molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) method. Our results show that the Pearson correlation coefficient in the modified MM/PBSA is over 0.70, which is much better than that in the standard MM/PBSA, especially in the Amber14SB force field. In particular, the performance of the standard MM/PBSA is very poor in a system where the proteins carry like charges. Moreover, we also calculated the mean absolute error (MAE) between the calculated and experimental Delta G values and found that the MAE in the modified MM/PBSA was indeed much smaller than that in the standard MM/PBSA. Furthermore, the effect of the dielectric constant of the proteins and the salt conditions on the results was also investigated. The present study highlights the potential power of the modified MM/PBSA for accurately predicting the binding energy in highly charged biosystems.

Automated summary

Accurate calculation of protein-protein binding free energy is crucial in biological and medical science, and a new strategy involving screened electrostatic energy has been developed in this study to improve the accuracy of calculations. The modified MM/PBSA method shows better correlation and smaller errors compared to the standard method, especially in systems with proteins carrying like charges. This study highlights the potential of the modified MM/PBSA in accurately predicting binding energies in highly charged biosystems.