title: A semiempirical approach to ligand-binding affinities: dependence on the Hamiltonian and corrections.
abstract: We present a combination of semiempirical quantum-mechanical (SQM) calculations in the conductor-like screening model with the MM/GBSA (molecular-mechanics with generalized Born and surface-area solvation) method for ligand-binding affinity calculations. We test three SQM Hamiltonians, AM1, RM1, and PM6, as well as hydrogen-bond corrections and two different dispersion corrections. As test cases, we use the binding of seven biotin analogues to avidin, nine inhibitors to factor Xa, and nine phenol-derivatives to ferritin. The results vary somewhat for the three test cases, but a dispersion correction is mandatory to reproduce experimental estimates. On average, AM1 with the DH2 hydrogen-bond and dispersion corrections gives the best results, which are similar to those of standard MM/GBSA calculations for the same systems. The total time consumption is only 1.3-1.6 times larger than for MM/GBSA.
authors.affiliation: Chemical Centre, Department of Theoretical Chemistry, Lund University, SE-221 00 Lund, Sweden.
authors.forename: Paulius
authors.initials: P
authors.lastname: Mikulskis
authors.forename: Samuel
authors.initials: S
authors.lastname: Genheden
authors.forename: Karin
authors.initials: K
authors.lastname: Wichmann
authors.forename: Ulf
authors.initials: U
authors.lastname: Ryde
mesh_terms: D001360:Avidin / Q000737:chemistry; D001710:Biotin / Q000031:analogs & derivatives / Q000737:chemistry; D015951:Factor Xa / Q000737:chemistry; D065427:Factor Xa Inhibitors / Q000737:chemistry; D005293:Ferritins / Q000737:chemistry; D008024:Ligands; D056004:Molecular Dynamics Simulation; D010636:Phenols / Q000737:chemistry; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry*; D011789:Quantum Theory; D013816:Thermodynamics
chemical_list: D065427:Factor Xa Inhibitors; D008024:Ligands; D010636:Phenols; D011506:Proteins; D001360:Avidin; D001710:Biotin; D005293:Ferritins; D015951:Factor Xa