title: Binding-affinity predictions of HSP90 in the D3R Grand Challenge 2015 with docking, MM/GBSA, QM/MM, and free-energy simulations.
abstract: We have estimated the binding affinity of three sets of ligands of the heat-shock protein 90 in the D3R grand challenge blind test competition. We have employed four different methods, based on five different crystal structures: first, we docked the ligands to the proteins with induced-fit docking with the Glide software and calculated binding affinities with three energy functions. Second, the docked structures were minimised in a continuum solvent and binding affinities were calculated with the MM/GBSA method (molecular mechanics combined with generalised Born and solvent-accessible surface area solvation). Third, the docked structures were re-optimised by combined quantum mechanics and molecular mechanics (QM/MM) calculations. Then, interaction energies were calculated with quantum mechanical calculations employing 970-1160 atoms in a continuum solvent, combined with energy corrections for dispersion, zero-point energy and entropy, ligand distortion, ligand solvation, and an increase of the basis set to quadruple-zeta quality. Fourth, relative binding affinities were estimated by free-energy simulations, using the multi-state Bennett acceptance-ratio approach. Unfortunately, the results were varying and rather poor, with only one calculation giving a correlation to the experimental affinities larger than 0.7, and with no consistent difference in the quality of the predictions from the various methods. For one set of ligands, the results could be strongly improved (after experimental data were revealed) if it was recognised that one of the ligands displaced one or two water molecules. For the other two sets, the problem is probably that the ligands bind in different modes than in the crystal structures employed or that the conformation of the ligand-binding site or the whole protein changes.
authors: Department of Theoretical Chemistry, Lund University, Chemical Centre, P. O. Box 124, 221 00, Lund, Sweden.
authors: Majda
authors: M
authors: Misini Ignjatović
authors: Department of Theoretical Chemistry, Lund University, Chemical Centre, P. O. Box 124, 221 00, Lund, Sweden.
authors: Octav
authors: O
authors: Caldararu
authors: Department of Theoretical Chemistry, Lund University, Chemical Centre, P. O. Box 124, 221 00, Lund, Sweden.
authors: Geng
authors: G
authors: Dong
authors: Centro de Bioinformática y Simulación Molecular, Facultad de Ingeniería, Universidad de Talca, 2 Norte 685, Talca, Chile.
authors: Camila
authors: C
authors: Muñoz-Gutierrez
authors: Centro de Bioinformática y Simulación Molecular, Facultad de Ingeniería, Universidad de Talca, 2 Norte 685, Talca, Chile.
authors: Francisco
authors: F
authors: Adasme-Carreño
authors: Department of Theoretical Chemistry, Lund University, Chemical Centre, P. O. Box 124, 221 00, Lund, Sweden. Ulf.Ryde@teokem.lu.se.
authors: Ulf
authors: 0000-0001-7653-8489
authors: U
authors: Ryde
mesh_terms: D001665:Binding Sites; D019277:Entropy; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry*; D006801:Humans; D007700:Kinetics; D008024:Ligands; D062105:Molecular Docking Simulation; D011485:Protein Binding; D011487:Protein Conformation; D012997:Solvents / Q000737:chemistry; D013816:Thermodynamics; D014867:Water / Q000737:chemistry
chemical_list: D018841:HSP90 Heat-Shock Proteins; D008024:Ligands; D012997:Solvents; D014867:Water
keywords: Bennett acceptance ratio; Big-QM; Blind-test competition; Continuum solvation; D3R grand challenge; Free-energy perturbation; Induced-fit docking; Ligand-binding affinity; MM/GBSA; QM/MM