Exposure of Von Willebrand Factor Cleavage Site in A1A2A3-Fragment under Extreme Hydrodynamic Shear

Von Willebrand Factor (vWf) is a giant multimeric extracellular blood plasma involved in hemostasis. In this work we present multi-scale simulations of its three-domains fragment A1A2A3. These three domains are essential for the functional regulation of vWf. Namely the A2 domain hosts the site where...

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Autores principales:	Olivier Languin-Cattoën, Emeline Laborie, Daria O. Yurkova, Simone Melchionna, Philippe Derreumaux, Aleksey V. Belyaev, Fabio Sterpone
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	von Willebrand factor molecular dynamics coarse-grains lattice Boltzmann shear flow protein unfolding Organic chemistry QD241-441
Acceso en línea:	https://doaj.org/article/b7568d091e654db79d0a0b88bae949b3
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spelling	oai:doaj.org-article:b7568d091e654db79d0a0b88bae949b32021-11-25T18:48:15ZExposure of Von Willebrand Factor Cleavage Site in A1A2A3-Fragment under Extreme Hydrodynamic Shear10.3390/polym132239122073-4360https://doaj.org/article/b7568d091e654db79d0a0b88bae949b32021-11-01T00:00:00Zhttps://www.mdpi.com/2073-4360/13/22/3912https://doaj.org/toc/2073-4360Von Willebrand Factor (vWf) is a giant multimeric extracellular blood plasma involved in hemostasis. In this work we present multi-scale simulations of its three-domains fragment A1A2A3. These three domains are essential for the functional regulation of vWf. Namely the A2 domain hosts the site where the protease ADAMTS13 cleavages the multimeric vWf allowing for its length control that prevents thrombotic conditions. The exposure of the cleavage site follows the elongation/unfolding of the domain that is caused by an increased shear stress in blood. By deploying Lattice Boltzmann molecular dynamics simulations based on the OPEP coarse-grained model for proteins, we investigated at molecular level the unfolding of the A2 domain under the action of a perturbing shear flow. We described the structural steps of this unfolding that mainly concerns the <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>β</mi></semantics></math></inline-formula>-strand structures of the domain, and we compared the process occurring under shear with that produced by the action of a directional pulling force, a typical condition of single molecule experiments. We observe, that under the action of shear flow, the competition among the elongational and rotational components of the fluid field leads to a complex behaviour of the domain, where elongated structures can be followed by partially collapsed melted globule structures with a very different degree of exposure of the cleavage site. Our simulations pose the base for the development of a multi-scale in-silico description of vWf dynamics and functionality in physiological conditions, including high resolution details for molecular relevant events, e.g., the binding to platelets and collagen during coagulation or thrombosis.Olivier Languin-CattoënEmeline LaborieDaria O. YurkovaSimone MelchionnaPhilippe DerreumauxAleksey V. BelyaevFabio SterponeMDPI AGarticlevon Willebrand factormolecular dynamicscoarse-grainslattice Boltzmannshear flowprotein unfoldingOrganic chemistryQD241-441ENPolymers, Vol 13, Iss 3912, p 3912 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	von Willebrand factor molecular dynamics coarse-grains lattice Boltzmann shear flow protein unfolding Organic chemistry QD241-441
spellingShingle	von Willebrand factor molecular dynamics coarse-grains lattice Boltzmann shear flow protein unfolding Organic chemistry QD241-441 Olivier Languin-Cattoën Emeline Laborie Daria O. Yurkova Simone Melchionna Philippe Derreumaux Aleksey V. Belyaev Fabio Sterpone Exposure of Von Willebrand Factor Cleavage Site in A1A2A3-Fragment under Extreme Hydrodynamic Shear
description	Von Willebrand Factor (vWf) is a giant multimeric extracellular blood plasma involved in hemostasis. In this work we present multi-scale simulations of its three-domains fragment A1A2A3. These three domains are essential for the functional regulation of vWf. Namely the A2 domain hosts the site where the protease ADAMTS13 cleavages the multimeric vWf allowing for its length control that prevents thrombotic conditions. The exposure of the cleavage site follows the elongation/unfolding of the domain that is caused by an increased shear stress in blood. By deploying Lattice Boltzmann molecular dynamics simulations based on the OPEP coarse-grained model for proteins, we investigated at molecular level the unfolding of the A2 domain under the action of a perturbing shear flow. We described the structural steps of this unfolding that mainly concerns the <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>β</mi></semantics></math></inline-formula>-strand structures of the domain, and we compared the process occurring under shear with that produced by the action of a directional pulling force, a typical condition of single molecule experiments. We observe, that under the action of shear flow, the competition among the elongational and rotational components of the fluid field leads to a complex behaviour of the domain, where elongated structures can be followed by partially collapsed melted globule structures with a very different degree of exposure of the cleavage site. Our simulations pose the base for the development of a multi-scale in-silico description of vWf dynamics and functionality in physiological conditions, including high resolution details for molecular relevant events, e.g., the binding to platelets and collagen during coagulation or thrombosis.
format	article
author	Olivier Languin-Cattoën Emeline Laborie Daria O. Yurkova Simone Melchionna Philippe Derreumaux Aleksey V. Belyaev Fabio Sterpone
author_facet	Olivier Languin-Cattoën Emeline Laborie Daria O. Yurkova Simone Melchionna Philippe Derreumaux Aleksey V. Belyaev Fabio Sterpone
author_sort	Olivier Languin-Cattoën
title	Exposure of Von Willebrand Factor Cleavage Site in A1A2A3-Fragment under Extreme Hydrodynamic Shear
title_short	Exposure of Von Willebrand Factor Cleavage Site in A1A2A3-Fragment under Extreme Hydrodynamic Shear
title_full	Exposure of Von Willebrand Factor Cleavage Site in A1A2A3-Fragment under Extreme Hydrodynamic Shear
title_fullStr	Exposure of Von Willebrand Factor Cleavage Site in A1A2A3-Fragment under Extreme Hydrodynamic Shear
title_full_unstemmed	Exposure of Von Willebrand Factor Cleavage Site in A1A2A3-Fragment under Extreme Hydrodynamic Shear
title_sort	exposure of von willebrand factor cleavage site in a1a2a3-fragment under extreme hydrodynamic shear
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/b7568d091e654db79d0a0b88bae949b3
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Exposure of Von Willebrand Factor Cleavage Site in A1A2A3-Fragment under Extreme Hydrodynamic Shear

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