A multiscale approach to modelling drug metabolism by membrane-bound cytochrome P450 enzymes.

Cytochrome P450 enzymes are found in all life forms. P450s play an important role in drug metabolism, and have potential uses as biocatalysts. Human P450s are membrane-bound proteins. However, the interactions between P450s and their membrane environment are not well-understood. To date, all P450 cr...

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Autores principales:	Richard Lonsdale, Sarah L Rouse, Mark S P Sansom, Adrian J Mulholland
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/46b6511e53aa496abe4abdd625f84e3a
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spelling	oai:doaj.org-article:46b6511e53aa496abe4abdd625f84e3a2021-11-25T05:40:57ZA multiscale approach to modelling drug metabolism by membrane-bound cytochrome P450 enzymes.1553-734X1553-735810.1371/journal.pcbi.1003714https://doaj.org/article/46b6511e53aa496abe4abdd625f84e3a2014-07-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/25033460/pdf/?tool=EBIhttps://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358Cytochrome P450 enzymes are found in all life forms. P450s play an important role in drug metabolism, and have potential uses as biocatalysts. Human P450s are membrane-bound proteins. However, the interactions between P450s and their membrane environment are not well-understood. To date, all P450 crystal structures have been obtained from engineered proteins, from which the transmembrane helix was absent. A significant number of computational studies have been performed on P450s, but the majority of these have been performed on the solubilised forms of P450s. Here we present a multiscale approach for modelling P450s, spanning from coarse-grained and atomistic molecular dynamics simulations to reaction modelling using hybrid quantum mechanics/molecular mechanics (QM/MM) methods. To our knowledge, this is the first application of such an integrated multiscale approach to modelling of a membrane-bound enzyme. We have applied this protocol to a key human P450 involved in drug metabolism: CYP3A4. A biologically realistic model of CYP3A4, complete with its transmembrane helix and a membrane, has been constructed and characterised. The dynamics of this complex have been studied, and the oxidation of the anticoagulant R-warfarin has been modelled in the active site. Calculations have also been performed on the soluble form of the enzyme in aqueous solution. Important differences are observed between the membrane and solution systems, most notably for the gating residues and channels that control access to the active site. The protocol that we describe here is applicable to other membrane-bound enzymes.Richard LonsdaleSarah L RouseMark S P SansomAdrian J MulhollandPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 10, Iss 7, p e1003714 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Richard Lonsdale Sarah L Rouse Mark S P Sansom Adrian J Mulholland A multiscale approach to modelling drug metabolism by membrane-bound cytochrome P450 enzymes.
description	Cytochrome P450 enzymes are found in all life forms. P450s play an important role in drug metabolism, and have potential uses as biocatalysts. Human P450s are membrane-bound proteins. However, the interactions between P450s and their membrane environment are not well-understood. To date, all P450 crystal structures have been obtained from engineered proteins, from which the transmembrane helix was absent. A significant number of computational studies have been performed on P450s, but the majority of these have been performed on the solubilised forms of P450s. Here we present a multiscale approach for modelling P450s, spanning from coarse-grained and atomistic molecular dynamics simulations to reaction modelling using hybrid quantum mechanics/molecular mechanics (QM/MM) methods. To our knowledge, this is the first application of such an integrated multiscale approach to modelling of a membrane-bound enzyme. We have applied this protocol to a key human P450 involved in drug metabolism: CYP3A4. A biologically realistic model of CYP3A4, complete with its transmembrane helix and a membrane, has been constructed and characterised. The dynamics of this complex have been studied, and the oxidation of the anticoagulant R-warfarin has been modelled in the active site. Calculations have also been performed on the soluble form of the enzyme in aqueous solution. Important differences are observed between the membrane and solution systems, most notably for the gating residues and channels that control access to the active site. The protocol that we describe here is applicable to other membrane-bound enzymes.
format	article
author	Richard Lonsdale Sarah L Rouse Mark S P Sansom Adrian J Mulholland
author_facet	Richard Lonsdale Sarah L Rouse Mark S P Sansom Adrian J Mulholland
author_sort	Richard Lonsdale
title	A multiscale approach to modelling drug metabolism by membrane-bound cytochrome P450 enzymes.
title_short	A multiscale approach to modelling drug metabolism by membrane-bound cytochrome P450 enzymes.
title_full	A multiscale approach to modelling drug metabolism by membrane-bound cytochrome P450 enzymes.
title_fullStr	A multiscale approach to modelling drug metabolism by membrane-bound cytochrome P450 enzymes.
title_full_unstemmed	A multiscale approach to modelling drug metabolism by membrane-bound cytochrome P450 enzymes.
title_sort	multiscale approach to modelling drug metabolism by membrane-bound cytochrome p450 enzymes.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/46b6511e53aa496abe4abdd625f84e3a
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A multiscale approach to modelling drug metabolism by membrane-bound cytochrome P450 enzymes.

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