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MD Simulations on a Well-Built Docking Model Reveal Fine Mechanical Stability and Force-Dependent Dissociation of Mac-1/GPIbα Complex

Interaction of leukocyte integrin macrophage-1 antigen (Mac-1) to platelet glycoprotein Ibα (GPIbα) is critical for platelet–leukocyte crosstalk in hemostasis and inflammatory responses to vessel injuries under hemodynamic environments. The mechano-regulation and its molecular basis for binding of M...

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Autores principales: Jiang, Xiaoyan, Sun, Xiaoxi, Lin, Jiangguo, Ling, Yingchen, Fang, Ying, Wu, Jianhua
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100526/
https://www.ncbi.nlm.nih.gov/pubmed/33968982
http://dx.doi.org/10.3389/fmolb.2021.638396
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author Jiang, Xiaoyan
Sun, Xiaoxi
Lin, Jiangguo
Ling, Yingchen
Fang, Ying
Wu, Jianhua
author_facet Jiang, Xiaoyan
Sun, Xiaoxi
Lin, Jiangguo
Ling, Yingchen
Fang, Ying
Wu, Jianhua
author_sort Jiang, Xiaoyan
collection PubMed
description Interaction of leukocyte integrin macrophage-1 antigen (Mac-1) to platelet glycoprotein Ibα (GPIbα) is critical for platelet–leukocyte crosstalk in hemostasis and inflammatory responses to vessel injuries under hemodynamic environments. The mechano-regulation and its molecular basis for binding of Mac-1 to GPIbα remain unclear, mainly coming from the lack of crystal structure of the Mac-1/GPIbα complex. We herein built a Mac-1/GPIbα complex model through a novel computer strategy, which included a flexible molecular docking and system equilibrium followed by a “force-ramp + snapback” molecular dynamics (MD) simulation. With this model, a series of “ramp-clamp” steered molecular dynamics (SMD) simulations were performed to examine the GPIbα–Mac-1 interaction under various loads. The results demonstrated that the complex was mechano-stable for both the high rupture force (>250 pN) at a pulling velocity of 3 Å/ns and the conformational conservation under various constant tensile forces (≤75 pN); a catch-slip bond transition was predicted through the dissociation probability, examined with single molecular AFM measurements, reflected by the interaction energy and the interface H-bond number, and related to the force-induced allostery of the complex; besides the mutation-identified residues D222 and R218, the residues were also dominant in the binding of Mac-1 to GPIbα. This study recommended a valid computer strategy for building a likely wild-type docking model of a complex, provided a novel insight into the mechanical regulation mechanism and its molecular basis for the interaction of Mac-1 with GPIbα, and would be helpful for understanding the platelet–leukocyte interaction in hemostasis and inflammatory responses under mechano-microenvironments.
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spelling pubmed-81005262021-05-07 MD Simulations on a Well-Built Docking Model Reveal Fine Mechanical Stability and Force-Dependent Dissociation of Mac-1/GPIbα Complex Jiang, Xiaoyan Sun, Xiaoxi Lin, Jiangguo Ling, Yingchen Fang, Ying Wu, Jianhua Front Mol Biosci Molecular Biosciences Interaction of leukocyte integrin macrophage-1 antigen (Mac-1) to platelet glycoprotein Ibα (GPIbα) is critical for platelet–leukocyte crosstalk in hemostasis and inflammatory responses to vessel injuries under hemodynamic environments. The mechano-regulation and its molecular basis for binding of Mac-1 to GPIbα remain unclear, mainly coming from the lack of crystal structure of the Mac-1/GPIbα complex. We herein built a Mac-1/GPIbα complex model through a novel computer strategy, which included a flexible molecular docking and system equilibrium followed by a “force-ramp + snapback” molecular dynamics (MD) simulation. With this model, a series of “ramp-clamp” steered molecular dynamics (SMD) simulations were performed to examine the GPIbα–Mac-1 interaction under various loads. The results demonstrated that the complex was mechano-stable for both the high rupture force (>250 pN) at a pulling velocity of 3 Å/ns and the conformational conservation under various constant tensile forces (≤75 pN); a catch-slip bond transition was predicted through the dissociation probability, examined with single molecular AFM measurements, reflected by the interaction energy and the interface H-bond number, and related to the force-induced allostery of the complex; besides the mutation-identified residues D222 and R218, the residues were also dominant in the binding of Mac-1 to GPIbα. This study recommended a valid computer strategy for building a likely wild-type docking model of a complex, provided a novel insight into the mechanical regulation mechanism and its molecular basis for the interaction of Mac-1 with GPIbα, and would be helpful for understanding the platelet–leukocyte interaction in hemostasis and inflammatory responses under mechano-microenvironments. Frontiers Media S.A. 2021-04-22 /pmc/articles/PMC8100526/ /pubmed/33968982 http://dx.doi.org/10.3389/fmolb.2021.638396 Text en Copyright © 2021 Jiang, Sun, Lin, Ling, Fang and Wu. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Molecular Biosciences
Jiang, Xiaoyan
Sun, Xiaoxi
Lin, Jiangguo
Ling, Yingchen
Fang, Ying
Wu, Jianhua
MD Simulations on a Well-Built Docking Model Reveal Fine Mechanical Stability and Force-Dependent Dissociation of Mac-1/GPIbα Complex
title MD Simulations on a Well-Built Docking Model Reveal Fine Mechanical Stability and Force-Dependent Dissociation of Mac-1/GPIbα Complex
title_full MD Simulations on a Well-Built Docking Model Reveal Fine Mechanical Stability and Force-Dependent Dissociation of Mac-1/GPIbα Complex
title_fullStr MD Simulations on a Well-Built Docking Model Reveal Fine Mechanical Stability and Force-Dependent Dissociation of Mac-1/GPIbα Complex
title_full_unstemmed MD Simulations on a Well-Built Docking Model Reveal Fine Mechanical Stability and Force-Dependent Dissociation of Mac-1/GPIbα Complex
title_short MD Simulations on a Well-Built Docking Model Reveal Fine Mechanical Stability and Force-Dependent Dissociation of Mac-1/GPIbα Complex
title_sort md simulations on a well-built docking model reveal fine mechanical stability and force-dependent dissociation of mac-1/gpibα complex
topic Molecular Biosciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100526/
https://www.ncbi.nlm.nih.gov/pubmed/33968982
http://dx.doi.org/10.3389/fmolb.2021.638396
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