Insertion of the Ca²⁺-independent phospholipase A₂ into a phospholipid bilayer via coarse-grained and atomistic molecular dynamics simulations.

Group VI Ca²⁺-independent phospholipase A₂ (iPLA₂) is a water-soluble enzyme that is active when associated with phospholipid membranes. Despite its clear pharmaceutical relevance, no X-ray or NMR structural information is currently available for the iPLA₂ or its membrane complex. In this paper, we...

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Autores principales:	Denis Bucher, Yuan-Hao Hsu, Varnavas D Mouchlis, Edward A Dennis, J Andrew McCammon
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/bae043e4bf034dd69d3f7bd5989398a8
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spelling	oai:doaj.org-article:bae043e4bf034dd69d3f7bd5989398a82021-11-18T05:53:42ZInsertion of the Ca²⁺-independent phospholipase A₂ into a phospholipid bilayer via coarse-grained and atomistic molecular dynamics simulations.1553-734X1553-735810.1371/journal.pcbi.1003156https://doaj.org/article/bae043e4bf034dd69d3f7bd5989398a82013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23935474/?tool=EBIhttps://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358Group VI Ca²⁺-independent phospholipase A₂ (iPLA₂) is a water-soluble enzyme that is active when associated with phospholipid membranes. Despite its clear pharmaceutical relevance, no X-ray or NMR structural information is currently available for the iPLA₂ or its membrane complex. In this paper, we combine homology modeling with coarse-grained (CG) and all-atom (AA) molecular dynamics (MD) simulations to build structural models of iPLA₂ in association with a phospholipid bilayer. CG-MD simulations of the membrane insertion process were employed to provide a starting point for an atomistic description. Six AA-MD simulations were then conducted for 60 ns, starting from different initial CG structures, to refine the membrane complex. The resulting structures are shown to be consistent with each other and with deuterium exchange mass spectrometry (DXMS) experiments, suggesting that our approach is suitable for the modeling of iPLA₂ at the membrane surface. The models show that an anchoring region (residues 710-724) forms an amphipathic helix that is stabilized by the membrane. In future studies, the proposed iPLA₂ models should provide a structural basis for understanding the mechanisms of lipid extraction and drug-inhibition. In addition, the dual-resolution approach discussed here should provide the means for the future exploration of the impact of lipid diversity and sequence mutations on the activity of iPLA₂ and related enzymes.Denis BucherYuan-Hao HsuVarnavas D MouchlisEdward A DennisJ Andrew McCammonPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 9, Iss 7, p e1003156 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Denis Bucher Yuan-Hao Hsu Varnavas D Mouchlis Edward A Dennis J Andrew McCammon Insertion of the Ca²⁺-independent phospholipase A₂ into a phospholipid bilayer via coarse-grained and atomistic molecular dynamics simulations.
description	Group VI Ca²⁺-independent phospholipase A₂ (iPLA₂) is a water-soluble enzyme that is active when associated with phospholipid membranes. Despite its clear pharmaceutical relevance, no X-ray or NMR structural information is currently available for the iPLA₂ or its membrane complex. In this paper, we combine homology modeling with coarse-grained (CG) and all-atom (AA) molecular dynamics (MD) simulations to build structural models of iPLA₂ in association with a phospholipid bilayer. CG-MD simulations of the membrane insertion process were employed to provide a starting point for an atomistic description. Six AA-MD simulations were then conducted for 60 ns, starting from different initial CG structures, to refine the membrane complex. The resulting structures are shown to be consistent with each other and with deuterium exchange mass spectrometry (DXMS) experiments, suggesting that our approach is suitable for the modeling of iPLA₂ at the membrane surface. The models show that an anchoring region (residues 710-724) forms an amphipathic helix that is stabilized by the membrane. In future studies, the proposed iPLA₂ models should provide a structural basis for understanding the mechanisms of lipid extraction and drug-inhibition. In addition, the dual-resolution approach discussed here should provide the means for the future exploration of the impact of lipid diversity and sequence mutations on the activity of iPLA₂ and related enzymes.
format	article
author	Denis Bucher Yuan-Hao Hsu Varnavas D Mouchlis Edward A Dennis J Andrew McCammon
author_facet	Denis Bucher Yuan-Hao Hsu Varnavas D Mouchlis Edward A Dennis J Andrew McCammon
author_sort	Denis Bucher
title	Insertion of the Ca²⁺-independent phospholipase A₂ into a phospholipid bilayer via coarse-grained and atomistic molecular dynamics simulations.
title_short	Insertion of the Ca²⁺-independent phospholipase A₂ into a phospholipid bilayer via coarse-grained and atomistic molecular dynamics simulations.
title_full	Insertion of the Ca²⁺-independent phospholipase A₂ into a phospholipid bilayer via coarse-grained and atomistic molecular dynamics simulations.
title_fullStr	Insertion of the Ca²⁺-independent phospholipase A₂ into a phospholipid bilayer via coarse-grained and atomistic molecular dynamics simulations.
title_full_unstemmed	Insertion of the Ca²⁺-independent phospholipase A₂ into a phospholipid bilayer via coarse-grained and atomistic molecular dynamics simulations.
title_sort	insertion of the ca²⁺-independent phospholipase a₂ into a phospholipid bilayer via coarse-grained and atomistic molecular dynamics simulations.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/bae043e4bf034dd69d3f7bd5989398a8
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Insertion of the Ca²⁺-independent phospholipase A₂ into a phospholipid bilayer via coarse-grained and atomistic molecular dynamics simulations.

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