Application of a SCC-DFTB QM/MM approach to the investigation of the catalytic mechanism of fatty acid amide hydrolase

Luigi Capoferri, Marco Mor, Jitnapa Sirirak, Ewa Chudyk, Adrian J. Mulholland, Alessio Lodola*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

13 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2375-2383
Number of pages9
JournalJournal of Molecular Modeling
Volume17
Issue number9
DOIs
Publication statusPublished - Sep 2011

Keywords

  • QM/MM
  • SCC-DFTB
  • FAAH
  • Reaction mechanism
  • Computational enzymology
  • FUNCTIONAL TIGHT-BINDING
  • QUANTUM-CHEMICAL METHODS
  • A BETA-LACTAMASE
  • ANTIBIOTIC-RESISTANCE
  • COMPUTER-SIMULATIONS
  • ENZYME CATALYSIS
  • DYNAMICS
  • SYSTEMS
  • DETERMINANTS

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