Molecular dynamics simulations of forced unbending of integrin α(v)β₃.

Integrins may undergo large conformational changes during activation, but the dynamic processes and pathways remain poorly understood. We used molecular dynamics to simulate forced unbending of a complete integrin α(v)β₃ ectodomain in both unliganded and liganded forms. Pulling the head of the integ...

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Autores principales:	Wei Chen, Jizhong Lou, Jen Hsin, Klaus Schulten, Stephen C Harvey, Cheng Zhu
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/51ed0a99986c488581ef0cf316ec36c0
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spelling	oai:doaj.org-article:51ed0a99986c488581ef0cf316ec36c02021-11-18T05:50:43ZMolecular dynamics simulations of forced unbending of integrin α(v)β₃.1553-734X1553-735810.1371/journal.pcbi.1001086https://doaj.org/article/51ed0a99986c488581ef0cf316ec36c02011-02-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21379327/?tool=EBIhttps://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358Integrins may undergo large conformational changes during activation, but the dynamic processes and pathways remain poorly understood. We used molecular dynamics to simulate forced unbending of a complete integrin α(v)β₃ ectodomain in both unliganded and liganded forms. Pulling the head of the integrin readily induced changes in the integrin from a bent to an extended conformation. Pulling at a cyclic RGD ligand bound to the integrin head also extended the integrin, suggesting that force can activate integrins. Interactions at the interfaces between the hybrid and β tail domains and between the hybrid and epidermal growth factor 4 domains formed the major energy barrier along the unbending pathway, which could be overcome spontaneously in ~1 µs to yield a partially-extended conformation that tended to rebend. By comparison, a fully-extended conformation was stable. A newly-formed coordination between the α(v) Asp457 and the α-genu metal ion might contribute to the stability of the fully-extended conformation. These results reveal the dynamic processes and pathways of integrin conformational changes with atomic details and provide new insights into the structural mechanisms of integrin activation.Wei ChenJizhong LouJen HsinKlaus SchultenStephen C HarveyCheng ZhuPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 7, Iss 2, p e1001086 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Wei Chen Jizhong Lou Jen Hsin Klaus Schulten Stephen C Harvey Cheng Zhu Molecular dynamics simulations of forced unbending of integrin α(v)β₃.
description	Integrins may undergo large conformational changes during activation, but the dynamic processes and pathways remain poorly understood. We used molecular dynamics to simulate forced unbending of a complete integrin α(v)β₃ ectodomain in both unliganded and liganded forms. Pulling the head of the integrin readily induced changes in the integrin from a bent to an extended conformation. Pulling at a cyclic RGD ligand bound to the integrin head also extended the integrin, suggesting that force can activate integrins. Interactions at the interfaces between the hybrid and β tail domains and between the hybrid and epidermal growth factor 4 domains formed the major energy barrier along the unbending pathway, which could be overcome spontaneously in ~1 µs to yield a partially-extended conformation that tended to rebend. By comparison, a fully-extended conformation was stable. A newly-formed coordination between the α(v) Asp457 and the α-genu metal ion might contribute to the stability of the fully-extended conformation. These results reveal the dynamic processes and pathways of integrin conformational changes with atomic details and provide new insights into the structural mechanisms of integrin activation.
format	article
author	Wei Chen Jizhong Lou Jen Hsin Klaus Schulten Stephen C Harvey Cheng Zhu
author_facet	Wei Chen Jizhong Lou Jen Hsin Klaus Schulten Stephen C Harvey Cheng Zhu
author_sort	Wei Chen
title	Molecular dynamics simulations of forced unbending of integrin α(v)β₃.
title_short	Molecular dynamics simulations of forced unbending of integrin α(v)β₃.
title_full	Molecular dynamics simulations of forced unbending of integrin α(v)β₃.
title_fullStr	Molecular dynamics simulations of forced unbending of integrin α(v)β₃.
title_full_unstemmed	Molecular dynamics simulations of forced unbending of integrin α(v)β₃.
title_sort	molecular dynamics simulations of forced unbending of integrin α(v)β₃.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/51ed0a99986c488581ef0cf316ec36c0
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Molecular dynamics simulations of forced unbending of integrin α(v)β₃.

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