Lü Shouqin, Long Mian
National Microgravity Laboratory, Institute of Mechanics, Chinese Academy of Sciences, Beijing 100080, P R China.
Mol Cell Biomech. 2005 Dec;2(4):161-77.
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 (sLe(X)), and E-LE with sLe(X). 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-LE-SGP-3 system mainly resulted from the destroy of the two anti-parallel beta 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.
选择素 - 配体相互作用对于诸如炎症级联反应或肿瘤转移等生物学过程至关重要。然而，血流中选择素 - 配体键的瞬时形成和解离如何在原子水平上与分子构象相耦合，目前尚未得到很好的理解。在本研究中，使用引导分子动力学（SMD）模拟来阐明三种选择素 - 配体系统强制解离过程中涉及的分子内和分子间构象演变：由P - 选择素凝集素（Lec）和表皮生长因子（EGF）样结构域组成的构建体（P - LE）与合成的硫代糖肽或SGP - 3相互作用、P - LE与唾液酸化路易斯X（sLe(X)）相互作用以及E - LE与sLe(X)相互作用。SMD模拟基于使用类比方法新建立的包括碳水化合物单元和硫酸化酪氨酸的力场参数。模拟结果表明，复合物的解离与分子伸展相关。在P - LE - SGP - 3系统中，分子内解缠主要源于EGF结构域的两个反平行β折叠的破坏以及Lec - EGF界面处氢键簇的断裂，而在所有三个系统中，分子间解离主要由岩藻糖（FUC）与Ca2 +离子的分离决定。强制解离过程中的构象变化取决于拉伸速度和力，以及力的施加方式。这项工作有助于更好地理解外力作用下选择素 - 配体相互作用的构象变化和粘附功能。
