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..
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Artikel |
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| Erscheinungsjahr: |
2011 |
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| Erschienen: |
2011 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:17 |
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| Enthalten in: |
Journal of molecular modeling - 17(2011), 9 vom: 02. März, Seite 2375-2383 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Capoferri, Luigi [VerfasserIn] |
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| Links: |
Volltext [lizenzpflichtig] |
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| Themen: |
| Anmerkungen: |
© Springer-Verlag 2011 |
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| doi: |
10.1007/s00894-011-0981-z |
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| 520 | |a 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. | ||
| 650 | 4 | |a QM/MM | |
| 650 | 4 | |a SCC-DFTB | |
| 650 | 4 | |a FAAH | |
| 650 | 4 | |a Reaction mechanism | |
| 650 | 4 | |a Computational enzymology | |
| 700 | 1 | |a Mor, Marco |4 aut | |
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| 700 | 1 | |a Chudyk, Ewa |4 aut | |
| 700 | 1 | |a Mulholland, Adrian J. |4 aut | |
| 700 | 1 | |a Lodola, Alessio |4 aut | |
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