Assessing the performance of the MM/PBSA and MM/GBSA methods. 10. Impacts of enhanced sampling and variable dielectric model on protein–protein Interactions

= -0.212). Two enhanced sampling methods (aMD and GaMD) are indeed more efficient for conformational sampling, but they did not improve the binding affinity predictions for protein-protein systems, suggesting that the aMD or GaMD sampling (at least in short timescale simulations) may not be a good choice for the MM/PBSA and MM/GBSA predictions of protein-protein complexes. The solute dielectric constant of 1.0 is recommended to MM/GBSA, but a higher solute dielectric constant is recommended to MM/PBSA, especially for the systems with higher polarity on the protein-protein binding interfaces. Then, a preliminary assessment of the MM/GBSA calculations based on a variable dielectric generalized Born (VDGB) model was conducted. The results highlight the potential power of VDGB in the free energy predictions for protein-protein systems, but more thorough studies should be done in the future.