Protein-Protein Binding Free Energy Predictions with the MM/PBSA Approach Complemented with the Gaussian-Based Method for Entropy Estimation.

Here, we present a Gaussian-based method for estimation of protein-protein binding entropy to augment the molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) method for computational prediction of binding free energy (Δ G ). The method is termed f5-MM/PBSA/E, where "E" stands for entropy and f5 for five adjustable parameters. The enthalpy components of Δ G (molecular mechanics, polar and non-polar solvation energies) are computed from a single implicit solvent generalized Born (GB) energy minimized structure of a protein-protein complex, while the binding entropy is computed using independently GB energy minimized unbound and bound structures. It should be emphasized that the f5-MM/PBSA/E method does not use snapshots, just energy minimized structures, and is thus very fast and computationally efficient. The method is trained and benchmarked in 5-fold validation test over a data set consisting of 46 protein-protein binding cases with experimentally determined dissociation constant K d values. This data set has been used for benchmarking in recently published protein-protein binding studies that apply conventional MM/PBSA and MM/PBSA with an enhanced sampling method. The f5-MM/PBSA/E tested on the same data set achieves similar or better performance than these computationally demanding approaches, making it an excellent choice for high throughput protein-protein binding affinity prediction studies.