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Molecular dynamics simulation of shear- and stretch-induced dissociation of P-selectin/PSGL-1 complex.

机译:P-选择素/ PSGL-1复合物的剪切和拉伸诱导解离的分子动力学模拟。

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By mediating the tethering and rolling of leukocytes on vascular surfaces, the interactions between P-selectin and the P-selectin glycoprotein ligand 1 (PSGL-1) play crucial roles during inflammation cascade. Tensile stretch produced by rolling leukocytes and shear stress exerted by blood flow constitute the two types of mechanical forces that act on the P-selectin/PSGL-1 bond. These forces modulate not only dissociation kinetics of this bond, but also the leukocyte adhesion dynamics. However, the respective contribution of the two forces to bond dissociation and to the corresponding microstructural bases remains unclear. To mimic the mechanical microenvironment, we developed two molecular dynamics approaches; namely, an approach involving the shear flow field with a controlled velocity gradient, and the track dragging approach with a defined trajectory. With each approach or with both combined, we investigate the microstructural evolution and dissociation kinetics of the P-LE/SGP-3 construct, which is the smallest functional unit of the P-selectin/PSGL-1 complex. The results demonstrate that both shear flow and tensile stretch play important roles in the collapse of the construct and that, before bond dissociation, the former causes more destruction of domains within the construct than the latter. Dissociation of the P-LE/SGP-3 construct features intramolecular destruction of the epidermal-growth-factor (EGF) domain and the breaking of hydrogen-bond clusters at the P-selectin-lectin/EGF interface. Thus, to better understand how mechanics impacts the dissociation kinetics of the P-selectin/PSGL-1 complex, we propose herein two approaches to mimic its physiological mechanical environment.
机译:通过介导血管表面白细胞的束缚和滚动,P-选择素与P-选择素糖蛋白配体1(PSGL-1)之间的相互作用在炎症级联过程中起着至关重要的作用。滚动白细胞产生的拉伸和血流施加的切应力构成作用于P-选择素/ PSGL-1键的两种机械力。这些力不仅调节该键的解离动力学,而且调节白细胞粘附动力学。然而,尚不清楚两种力对键解离和对相应的微结构基础的各自贡献。为了模拟机械微环境,我们开发了两种分子动力学方法:也就是说,一种方法是将剪切流场控制在速度梯度范围之内,而将轨道拖入的方法则采用规定的轨迹。每种方法或两种方法结合使用,我们研究P-LE / SGP-3构建体的微观结构演变和解离动力学,该构建体是P-选择素/ PSGL-1复合体的最小功能单元。结果表明,剪切流和拉伸拉伸都在构建体的坍塌中起重要作用,并且在键解离之前,前者比后者导致更多的结构域破坏。 P-LE / SGP-3构建体的解离的特征是表皮生长因子(EGF)域的分子内破坏和P-选择素-凝集素/ EGF界面处的氢键簇断裂。因此,为了更好地理解力学如何影响P-选择蛋白/ PSGL-1复合物的解离动力学,我们在本文中提出了两种模拟其生理机械环境的方法。

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