Assessment of a mechanism for reactive inhibition of carboxypeptidase a with QM/MM methods

Lily Phoon; Neil A. Burton

doi:10.1016/j.jmgm.2005.06.004

Assessment of a mechanism for reactive inhibition of carboxypeptidase a with QM/MM methods

Lily Phoon, Neil A. Burton

Research output: Contribution to journal › Article › peer-review

Abstract

The mechanism for inhibition of carboxypeptidase A (CPA) by the two enantiomers of a reactive inhibitor, N-(2-chloroethyl)-N-methylphenylalanine, has been investigated using computational methods. Quantum mechanical and molecular mechanical (QM/MM) methods have been employed to find likely enzyme binding conformations by comparison with the observed rates of inactivation of the enzyme. The study has shown that the enzyme active site appears to be flexible enough to allow the nucleophilic deactivation reactions of both the (R) and (S) forms of a model of the inhibitor to be catalysed by the Zn(II) cofactor of CPA. © 2005 Elsevier Inc. All rights reserved.

Original language	English
Pages (from-to)	94-101
Number of pages	7
Journal	Journal of Molecular Graphics and Modelling
Volume	24
Issue number	2
DOIs	https://doi.org/10.1016/j.jmgm.2005.06.004
Publication status	Published - Oct 2005

Keywords

Carboxypeptidase A
Density functional theory
Enantiomer binding
Enzyme inhibition
N-(2-Chloroethyl)-N-methylphenylalanine
QM/MM
Reactive inhibition

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10.1016/j.jmgm.2005.06.004

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title = "Assessment of a mechanism for reactive inhibition of carboxypeptidase a with QM/MM methods",

abstract = "The mechanism for inhibition of carboxypeptidase A (CPA) by the two enantiomers of a reactive inhibitor, N-(2-chloroethyl)-N-methylphenylalanine, has been investigated using computational methods. Quantum mechanical and molecular mechanical (QM/MM) methods have been employed to find likely enzyme binding conformations by comparison with the observed rates of inactivation of the enzyme. The study has shown that the enzyme active site appears to be flexible enough to allow the nucleophilic deactivation reactions of both the (R) and (S) forms of a model of the inhibitor to be catalysed by the Zn(II) cofactor of CPA. {\textcopyright} 2005 Elsevier Inc. All rights reserved.",

keywords = "Carboxypeptidase A, Density functional theory, Enantiomer binding, Enzyme inhibition, N-(2-Chloroethyl)-N-methylphenylalanine, QM/MM, Reactive inhibition",

author = "Lily Phoon and Burton, {Neil A.}",

year = "2005",

month = oct,

doi = "10.1016/j.jmgm.2005.06.004",

language = "English",

volume = "24",

pages = "94--101",

journal = "Journal of Molecular Graphics and Modelling",

issn = "1093-3263",

publisher = "Elsevier BV",

number = "2",

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TY - JOUR

T1 - Assessment of a mechanism for reactive inhibition of carboxypeptidase a with QM/MM methods

AU - Phoon, Lily

AU - Burton, Neil A.

PY - 2005/10

Y1 - 2005/10

N2 - The mechanism for inhibition of carboxypeptidase A (CPA) by the two enantiomers of a reactive inhibitor, N-(2-chloroethyl)-N-methylphenylalanine, has been investigated using computational methods. Quantum mechanical and molecular mechanical (QM/MM) methods have been employed to find likely enzyme binding conformations by comparison with the observed rates of inactivation of the enzyme. The study has shown that the enzyme active site appears to be flexible enough to allow the nucleophilic deactivation reactions of both the (R) and (S) forms of a model of the inhibitor to be catalysed by the Zn(II) cofactor of CPA. © 2005 Elsevier Inc. All rights reserved.

AB - The mechanism for inhibition of carboxypeptidase A (CPA) by the two enantiomers of a reactive inhibitor, N-(2-chloroethyl)-N-methylphenylalanine, has been investigated using computational methods. Quantum mechanical and molecular mechanical (QM/MM) methods have been employed to find likely enzyme binding conformations by comparison with the observed rates of inactivation of the enzyme. The study has shown that the enzyme active site appears to be flexible enough to allow the nucleophilic deactivation reactions of both the (R) and (S) forms of a model of the inhibitor to be catalysed by the Zn(II) cofactor of CPA. © 2005 Elsevier Inc. All rights reserved.

KW - Carboxypeptidase A

KW - Density functional theory

KW - Enantiomer binding

KW - Enzyme inhibition

KW - N-(2-Chloroethyl)-N-methylphenylalanine

KW - QM/MM

KW - Reactive inhibition

U2 - 10.1016/j.jmgm.2005.06.004

DO - 10.1016/j.jmgm.2005.06.004

M3 - Article

SN - 1093-3263

VL - 24

SP - 94

EP - 101

JO - Journal of Molecular Graphics and Modelling

JF - Journal of Molecular Graphics and Modelling

IS - 2

ER -

Assessment of a mechanism for reactive inhibition of carboxypeptidase a with QM/MM methods

Abstract

Keywords

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