Forced Dissociation of Selectin-ligand Complexes Using Steered Molecular Dynamics Simulation

Selectin-ligand interactions are crucial to such biological processes as inflammatory cascade or tumor metastasis. How transient formation and dissociation of selectin-ligand bonds in blood flow are coupled to molecular conformation at atomic level, however, has not been well understood. In this study, steered molecular dynamics (SMD) simulations were used to elucidate the intramolecular and intermolecular conformational evolutions involved in forced dissociation of three selectin-ligand systems: the construct consisting of P-selectin lectin (Lec) and epidermal growth factor (EGF)-like domains (P-LE) interacting with synthesized sulfoglycopeptide or SGP-3, P-LE with sialyl Lewis X (sLeX), and E-LE with sLeX. SMD simulations were based on newly built-up force field parameters including carbohydrate units and sulfated tyrosine(s) using an analogy approach. The simulations demonstrated that the complex dissociation was coupled to the molecular extension. While the intramolecular unraveling in P-LESGP-3 system mainly resulted from the destroy of the two anti-parallel sheets of EGF domain and the breakage of hydrogen-bond cluster at the Lec-EGF interface, the intermolecular dissociation was mainly determined by separation of fucose (FUC) from Ca2+ ion in all three systems. Conformational changes during forced dissociations depended on pulling velocities and forces, as well as on how the force was applied. This work provides an insight into better understanding of conformational changes and adhesive functionality of selectin-ligand interactions under external forces.

PSGL-1酪氨酸变异体的动力学分析

<正>在炎症反应过程中,选择素/配体相互作用介导了白细胞在血管内皮表面的滚动和结合。选择素/配体相互作用的化学反应速率、反应亲和性和力学强度对白细胞的滚动起决定性作用。选择素家族的所有成员(P-、E-、和L-选择素)都有一个共同的配体PSGL-1(P-selectinglycoproteinligand-1)——一种白细胞表面的同源双体粘液素蛋白。PSGL-1与P-或L-选择素发生粘附需要同时含有两个必要结构:46、48和51位酪氨酸的硫酸化;57位苏氨酸的0型糖苷,并经过sLe~x(sialyl