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 ΔG 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.