Fragment-based Quantum Mechanical Calculation Of Protein-protein Binding Affinities

The electrostatically embedded generalized molecular fractionation with conjugate caps(EE-GMFCC)method has been successfully utilized for efficient linear-scaling quantum mechanical(QM)calculation of protein energies.In this work,we applied the EE-GMFCC method for calculation of binding affinity of Endonuclease colicinimmunity protein complex.The binding free energy changes between the wild-type and mutants of the complex calculated by EE-GMFCC are in good agreement with experimental results.The correlation coefficient(R)between the predicted binding energy changes and experimental values is 0.906 at the B3LYP/6-31G*-D level,based on the snapshot whose binding affinity is closest to the average result from the molecular mechanics/Poisson-Boltzmann surface area(MM/PBSA)calculation.The inclusion of the QM effects is important for accurate prediction of protein-protein binding affinities.Moreover,the self-consistent calculation of PB solvation energy is required for accurate calculations of protein-protein binding free energies.The current study demonstrates that the EE-GMFCC method is capable of providing reliable prediction of relative binding affinities for protein-protein complexes.