title: A QM/MM study of fluoroaromatic interactions at the binding site of carbonic anhydrase II, using a DFT method corrected for dispersive interactions.
abstract: The interaction of the fluorinated benzyl ring of a series of inhibitors of carbonic anhydrase II (CAII), fluorine-substituted N-(4-sulfamylbenzoyl)benzylamines (SBB), with nearby residues in the active site has been studied using a hybrid QM/MM model. To account for the important dispersive interactions between the fluorinated benzenes and these residues, a density functional method with an empirical dispersive term, (DFT-D), is used as the QM part of the model. The major interactions are found to be between the substituted benzenes and the aromatic ring of a nearby phenylalanine residue. However, the intermolecular separations between these two groups span a greater range than that found for comparable interactions between isolated molecules, showing the importance of interactions with other residues, which have been quantified. A decomposition of the interaction energy between the fluorobenzenes and each residue has been carried out which shows the dispersive interactions to be dominant. This work has shown that a QM(DFT-D)/MM model is a computationally feasible and accurate way of studying substrate-protein interactions.
authors.affiliation: School of Chemistry, University of Manchester, Manchester, UK.
authors.forename: Claudio A
authors.initials: CA
authors.lastname: Morgado
authors.forename: Ian H
authors.initials: IH
authors.lastname: Hillier
authors.forename: Neil A
authors.initials: NA
authors.lastname: Burton
authors.forename: Joseph J W
authors.initials: JJ
authors.lastname: McDouall
mesh_terms: D001554:Benzene / Q000737:chemistry; D001665:Binding Sites; D024402:Carbonic Anhydrase II / Q000737:chemistry* / Q000378:metabolism; D003500:Cyclization; D008024:Ligands; D008958:Models, Molecular; D011789:Quantum Theory
chemical_list: D008024:Ligands; D024402:Carbonic Anhydrase II; D001554:Benzene