title: Toward on-the-fly quantum mechanical/molecular mechanical (QM/MM) docking: development and benchmark of a scoring function.
abstract: We address the challenges of treating polarization and covalent interactions in docking by developing a hybrid quantum mechanical/molecular mechanical (QM/MM) scoring function based on the semiempirical self-consistent charge density functional tight-binding (SCC-DFTB) method and the CHARMM force field. To benchmark this scoring function within the EADock DSS docking algorithm, we created a publicly available dataset of high-quality X-ray structures of zinc metalloproteins ( http://www.molecular-modelling.ch/resources.php ). For zinc-bound ligands (226 complexes), the QM/MM scoring yielded a substantially improved success rate compared to the classical scoring function (77.0% vs 61.5%), while, for allosteric ligands (55 complexes), the success rate remained constant (49.1%). The QM/MM scoring significantly improved the detection of correct zinc-binding geometries and improved the docking success rate by more than 20% for several important drug targets. The performance of both the classical and the QM/MM scoring functions compare favorably to the performance of AutoDock4, AutoDock4Zn, and AutoDock Vina.
authors.affiliation: Swiss Institute of Bioinformatics , Molecular Modeling Group, Quartier Sorge, Bâtiment Génopode, CH-1015 Lausanne, Switzerland.
authors.forename: Prasad
authors.initials: P
authors.lastname: Chaskar
authors.forename: Vincent
authors.initials: V
authors.lastname: Zoete
authors.forename: Ute F
authors.initials: UF
authors.lastname: Röhrig
mesh_terms: D051722:ADAM Proteins / Q000737:chemistry / Q000378:metabolism; D000072198:ADAM17 Protein; D000465:Algorithms; D019985:Benchmarking; D002256:Carbonic Anhydrases / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D008667:Metalloproteins / Q000737:chemistry / Q000378:metabolism; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D011789:Quantum Theory; D013816:Thermodynamics; D015032:Zinc / Q000378:metabolism
chemical_list: D008667:Metalloproteins; D051722:ADAM Proteins; D000072198:ADAM17 Protein; D002256:Carbonic Anhydrases; D015032:Zinc