Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Jiang X

PROVIDER: S-EPMC8100526 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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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.

Jiang Xiaoyan X Sun Xiaoxi X Lin Jiangguo J Ling Yingchen Y Fang Ying Y Wu Jianhua J

Frontiers in molecular biosciences 20210422

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 ...[more]

PMID: 33968982

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Project description:The presumptive function for alpha-tocopherol (αtoc) in membranes is to protect polyunsaturated lipids against oxidation. Although the chemistry of the process is well established, the role played by molecular structure that we address here with atomistic molecular-dynamics simulations remains controversial. The simulations were run in the constant particle NPT ensemble on hydrated lipid bilayers composed of SDPC (1-stearoyl-2-docosahexaenoylphosphatidylcholine, 18:0-22:6PC) and SOPC (1-stearoyl-2-oleoylphosphatidylcholine, 18:0-18:1PC) in the presence of 20 mol % αtoc at 37°C. SDPC with SA (stearic acid) for the sn-1 chain and DHA (docosahexaenoic acid) for the sn-2 chain is representative of polyunsaturated phospholipids, while SOPC with OA (oleic acid) substituted for the sn-2 chain serves as a monounsaturated control. Solid-state (2)H nuclear magnetic resonance and neutron diffraction experiments provide validation. The simulations demonstrate that high disorder enhances the probability that DHA chains at the sn-2 position in SDPC rise up to the bilayer surface, whereby they encounter the chromanol group on αtoc molecules. This behavior is reflected in the van der Waals energy of interaction between αtoc and acyl chains, and illustrated by density maps of distribution for acyl chains around αtoc molecules that were constructed. An ability to more easily penetrate deep into the bilayer is another attribute conferred upon the chromanol group in αtoc by the high disorder possessed by DHA. By examining the trajectory of single molecules, we found that αtoc flip-flops across the SDPC bilayer on a submicrosecond timescale that is an order-of-magnitude greater than in SOPC. Our results reveal mechanisms by which the sacrificial hydroxyl group on the chromanol group can trap lipid peroxyl radicals within the interior and near the surface of a polyunsaturated membrane. At the same time, water-soluble reducing agents that regenerate αtoc can access the chromanol group when it locates at the surface.

Dataset Information

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

Publications

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

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