title: The MM2QM tool for combining docking, molecular dynamics, molecular mechanics, and quantum mechanics.
abstract: The use of the MM2QM tool in a combined docking + molecular dynamics (MD) + molecular mechanics (MM) + quantum mechanical (QM) binding affinity prediction study is presented, and the tool itself is discussed. The system of interest is Mycobacterium tuberculosis (MTB) pantothenate synthetase in complexes with three highly similar sulfonamide inhibitors, for which crystal structures are available. Starting from the structure of MTB pantothenate synthetase in the "open" conformation and following the combined docking + MD + MM + QM procedure, we were able to capture the closing of the enzyme binding pocket and to reproduce the position of the ligands with an average root mean square deviation of 1.6 Å. Protein-ligand interaction energies were reproduced with an average error lower than 10%. The discussion on the MD part and a protein flexibility importance is carried out. The presented approach may be useful especially for finding analog inhibitors or improving drug candidates.
authors.affiliation: Institute for Medical Biology of the Polish Academy of Sciences, Lodowa 106, Łódź 93-232, Poland. marcinn@bioinfo.pl
authors.forename: Marcin
authors.initials: M
authors.lastname: Nowosielski
authors.forename: Marcin
authors.initials: M
authors.lastname: Hoffmann
authors.forename: Aneta
authors.initials: A
authors.lastname: Kuron
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Korycka-Machala
authors.forename: Jaroslaw
authors.initials: J
authors.lastname: Dziadek
mesh_terms: D000995:Antitubercular Agents / Q000737:chemistry*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000737:chemistry*; D008024:Ligands; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009169:Mycobacterium tuberculosis / Q000737:chemistry* / Q000201:enzymology; D010453:Peptide Synthases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D011485:Protein Binding; D011789:Quantum Theory; D012984:Software; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D008024:Ligands; D013449:Sulfonamides; D010453:Peptide Synthases; C022318:pantothenate synthetase