title: Application of a SCC-DFTB QM/MM approach to the investigation of the catalytic mechanism of fatty acid amide hydrolase.
abstract: Self-consistent charge density functional tight binding (SCC-DFTB) is a promising method for hybrid quantum mechanics/molecular mechanics (QM/MM) simulations of enzyme-catalyzed reactions. The acylation reaction of fatty acid amide hydrolase (FAAH), a promising drug target, was investigated by applying a SCC-DFTB/CHARMM27 scheme. Calculated potential energy barriers resulted in reasonable agreement with experiments for oleamide (OA) and oleoylmethyl ester (OME) substrates, outperforming previous calculations performed at the PM3/CHARMM22 level. Furthermore, the experimental preference of FAAH in hydrolyzing OA faster than OME was adequately reproduced by calculations. All these findings indicate that the SCC-DFTB/CHARMM27 approach can be successfully applied to mechanistic investigations of FAAH-catalyzed reactions.
authors.affiliation: Dipartimento Farmaceutico, Università degli Studi di Parma, viale G. P. Usberti 27/A Campus Universitario, 43124, Parma, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Capoferri
authors.forename: Marco
authors.initials: M
authors.lastname: Mor
authors.forename: Jitnapa
authors.initials: J
authors.lastname: Sirirak
authors.forename: Ewa
authors.initials: E
authors.lastname: Chudyk
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Mulholland
authors.forename: Alessio
authors.initials: A
authors.lastname: Lodola
mesh_terms: D000215:Acylation; D000581:Amidohydrolases / Q000737:chemistry*; D020816:Amino Acid Motifs; D055162:Biocatalysis; D020134:Catalytic Domain; D008956:Models, Chemical; D056004:Molecular Dynamics Simulation; D011789:Quantum Theory; D013816:Thermodynamics; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D000099252:Fatty Acid Amide Hydrolases