Article: article from journal or magazin.
Toward on-the-fly quantum mechanical/molecular mechanical (QM/MM) docking: development and benchmark of a scoring function.
Journal of Chemical Information and Modeling
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.
ADAM Proteins/chemistry, ADAM Proteins/metabolism, Algorithms, Benchmarking, Carbonic Anhydrases/chemistry, Carbonic Anhydrases/metabolism, Drug Design, Metalloproteins/chemistry, Metalloproteins/metabolism, Molecular Docking Simulation, Protein Conformation, Quantum Theory, Thermodynamics, Zinc/metabolism
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