Protein/ligand binding free energies calculated with quantum mechanics/molecular mechanics.
Fiche publication
Date publication
mai 2005
Auteurs
Membres identifiés du Cancéropôle Est :
Dr DEJAEGERE Annick
Tous les auteurs :
Grater F, Schwarzl SM, Dejaegere A, Fischer S, Smith JC
Lien Pubmed
Résumé
The calculation of binding affinities for flexible ligands has hitherto required the availability of reliable molecular mechanics parameters for the ligands, a restriction that can in principle be lifted by using a mixed quantum mechanics/molecular mechanics (QM/MM) representation in which the ligand is treated quantum mechanically. The feasibility of this approach is evaluated here, combining QM/MM with the Poisson-Boltzmann/surface area model of continuum solvation and testing the method on a set of 47 benzamidine derivatives binding to trypsin. The experimental range of the absolute binding energy (DeltaG = -3.9 to -7.6 kcal/mol) is reproduced well, with a root-mean-square (RMS) error of 1.2 kcal/mol. When QM/MM is applied without reoptimization to the very different ligands of FK506 binding protein the RMS error is only 0.7 kcal/mol. The results show that QM/MM is a promising new avenue for automated docking and scoring of flexible ligands. Suggestions are made for further improvements in accuracy.
Référence
J Phys Chem B. 2005 May 26;109(20):10474-83.