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

doi:10.1007/s00894-011-0981-z

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 journal › Article (Academic Journal) › peer-review

19 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 language	English
Pages (from-to)	2375-2383
Number of pages	9
Journal	Journal of Molecular Modeling
Volume	17
Issue number	9
DOIs	https://doi.org/10.1007/s00894-011-0981-z
Publication status	Published - Sept 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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COMPUTATIONAL BIOCHEMISTRY: PREDICTIVE MODELLING FOR BIOLOGY AND MEDICINE
Mulholland, A. J. (Principal Investigator)
1/10/08 → 1/04/14
Project: Research

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@article{578ab1144a1342a195c3bd0474036164,

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.",

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",

author = "Luigi Capoferri and Marco Mor and Jitnapa Sirirak and Ewa Chudyk and Mulholland, {Adrian J.} and Alessio Lodola",

year = "2011",

month = sep,

doi = "10.1007/s00894-011-0981-z",

language = "English",

volume = "17",

pages = "2375--2383",

journal = "Journal of Molecular Modeling",

issn = "1610-2940",

publisher = "Springer Berlin Heidelberg",

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TY - JOUR

T1 - Application of a SCC-DFTB QM/MM approach to the investigation of the catalytic mechanism of fatty acid amide hydrolase

AU - Capoferri, Luigi

AU - Mor, Marco

AU - Sirirak, Jitnapa

AU - Chudyk, Ewa

AU - Mulholland, Adrian J.

AU - Lodola, Alessio

PY - 2011/9

Y1 - 2011/9

N2 - 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.

AB - 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.

KW - QM/MM

KW - SCC-DFTB

KW - FAAH

KW - Reaction mechanism

KW - Computational enzymology

KW - FUNCTIONAL TIGHT-BINDING

KW - QUANTUM-CHEMICAL METHODS

KW - A BETA-LACTAMASE

KW - ANTIBIOTIC-RESISTANCE

KW - COMPUTER-SIMULATIONS

KW - ENZYME CATALYSIS

KW - DYNAMICS

KW - SYSTEMS

KW - DETERMINANTS

U2 - 10.1007/s00894-011-0981-z

DO - 10.1007/s00894-011-0981-z

M3 - Article (Academic Journal)

C2 - 21365225

SN - 1610-2940

VL - 17

SP - 2375

EP - 2383

JO - Journal of Molecular Modeling

JF - Journal of Molecular Modeling

IS - 9

ER -

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

Abstract

Keywords

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COMPUTATIONAL BIOCHEMISTRY: PREDICTIVE MODELLING FOR BIOLOGY AND MEDICINE

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