Insertion of the Ca(2+)-Independent Phospholipase A(2) into a Phospholipid Bilayer via Coarse-Grained and Atomistic Molecular Dynamics Simulations

Group VI Ca(2+)-independent phospholipase A(2) (iPLA(2)) 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 iPLA(2) or its membrane complex. In this pa...

Descripción completa

Detalles Bibliográficos
Autores principales: Bucher, Denis, Hsu, Yuan-Hao, Mouchlis, Varnavas D., Dennis, Edward A., McCammon, J. Andrew
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3723492/
https://www.ncbi.nlm.nih.gov/pubmed/23935474
http://dx.doi.org/10.1371/journal.pcbi.1003156
_version_ 1782278282576658432
author Bucher, Denis
Hsu, Yuan-Hao
Mouchlis, Varnavas D.
Dennis, Edward A.
McCammon, J. Andrew
author_facet Bucher, Denis
Hsu, Yuan-Hao
Mouchlis, Varnavas D.
Dennis, Edward A.
McCammon, J. Andrew
author_sort Bucher, Denis
collection PubMed
description Group VI Ca(2+)-independent phospholipase A(2) (iPLA(2)) 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 iPLA(2) 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 iPLA(2) 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 iPLA(2) 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 iPLA(2) 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 iPLA(2) and related enzymes.
format Online
Article
Text
id pubmed-3723492
institution National Center for Biotechnology Information
language English
publishDate 2013
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-37234922013-08-09 Insertion of the Ca(2+)-Independent Phospholipase A(2) into a Phospholipid Bilayer via Coarse-Grained and Atomistic Molecular Dynamics Simulations Bucher, Denis Hsu, Yuan-Hao Mouchlis, Varnavas D. Dennis, Edward A. McCammon, J. Andrew PLoS Comput Biol Research Article Group VI Ca(2+)-independent phospholipase A(2) (iPLA(2)) 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 iPLA(2) 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 iPLA(2) 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 iPLA(2) 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 iPLA(2) 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 iPLA(2) and related enzymes. Public Library of Science 2013-07-25 /pmc/articles/PMC3723492/ /pubmed/23935474 http://dx.doi.org/10.1371/journal.pcbi.1003156 Text en © 2013 Bucher et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Bucher, Denis
Hsu, Yuan-Hao
Mouchlis, Varnavas D.
Dennis, Edward A.
McCammon, J. Andrew
Insertion of the Ca(2+)-Independent Phospholipase A(2) into a Phospholipid Bilayer via Coarse-Grained and Atomistic Molecular Dynamics Simulations
title Insertion of the Ca(2+)-Independent Phospholipase A(2) into a Phospholipid Bilayer via Coarse-Grained and Atomistic Molecular Dynamics Simulations
title_full Insertion of the Ca(2+)-Independent Phospholipase A(2) into a Phospholipid Bilayer via Coarse-Grained and Atomistic Molecular Dynamics Simulations
title_fullStr Insertion of the Ca(2+)-Independent Phospholipase A(2) into a Phospholipid Bilayer via Coarse-Grained and Atomistic Molecular Dynamics Simulations
title_full_unstemmed Insertion of the Ca(2+)-Independent Phospholipase A(2) into a Phospholipid Bilayer via Coarse-Grained and Atomistic Molecular Dynamics Simulations
title_short Insertion of the Ca(2+)-Independent Phospholipase A(2) into a Phospholipid Bilayer via Coarse-Grained and Atomistic Molecular Dynamics Simulations
title_sort insertion of the ca(2+)-independent phospholipase a(2) into a phospholipid bilayer via coarse-grained and atomistic molecular dynamics simulations
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3723492/
https://www.ncbi.nlm.nih.gov/pubmed/23935474
http://dx.doi.org/10.1371/journal.pcbi.1003156
work_keys_str_mv AT bucherdenis insertionoftheca2independentphospholipasea2intoaphospholipidbilayerviacoarsegrainedandatomisticmoleculardynamicssimulations
AT hsuyuanhao insertionoftheca2independentphospholipasea2intoaphospholipidbilayerviacoarsegrainedandatomisticmoleculardynamicssimulations
AT mouchlisvarnavasd insertionoftheca2independentphospholipasea2intoaphospholipidbilayerviacoarsegrainedandatomisticmoleculardynamicssimulations
AT dennisedwarda insertionoftheca2independentphospholipasea2intoaphospholipidbilayerviacoarsegrainedandatomisticmoleculardynamicssimulations
AT mccammonjandrew insertionoftheca2independentphospholipasea2intoaphospholipidbilayerviacoarsegrainedandatomisticmoleculardynamicssimulations