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

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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.

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Acknowledgments

AJM and EC thank the Engineering and Physical Science Research Council for support. AJM is an Engineering and Physical Science Research Council Leadership Fellow. JS thanks the Royal Thai Government for funding.

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Authors and Affiliations

  1. Dipartimento Farmaceutico, Università degli Studi di Parma, viale G. P. Usberti 27/A Campus Universitario, 43124, Parma, Italy

    Luigi Capoferri, Marco Mor & Alessio Lodola

  2. Centre for Computational Chemistry School of Chemistry, University of Bristol, Bristol, BS8 1TS, UK

    Jitnapa Sirirak, Ewa Chudyk & Adrian J. Mulholland

Authors
  1. Luigi Capoferri
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  2. Marco Mor
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  3. Jitnapa Sirirak
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  4. Ewa Chudyk
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  5. Adrian J. Mulholland
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  6. Alessio Lodola
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Corresponding authors

Correspondence to Adrian J. Mulholland or Alessio Lodola.

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Capoferri, L., Mor, M., Sirirak, J. et al. Application of a SCC-DFTB QM/MM approach to the investigation of the catalytic mechanism of fatty acid amide hydrolase. J Mol Model 17, 2375–2383 (2011). https://doi.org/10.1007/s00894-011-0981-z

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  • DOI: https://doi.org/10.1007/s00894-011-0981-z

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