细胞黏附复合物的强制破裂揭示了两种脆性状态之间的突然转换
Forced-rupture of Cell-Adhesion Complexes Reveals abrupt switch between two Brittle States
摘要：
细胞黏附复合物（celladhesioncomplex，CACs）通过与配体结合而被激活，在细胞周期调控和细胞外基质粘附等细胞功能中发挥重要作用。受白细胞功能相关抗原-1（LFA-1）的单分子拉伸实验的启发，该抗原在T细胞中表达，与细胞间粘附分子（ICAM）结合，我们使用自组织聚合物（SOP）模型进行恒定加载速率（$r_f$）和恒定力（$F$）模拟以描述配体从CAC断裂的机制。模拟再现的主要实验发现的动力学的破裂过程，即，最可能的破裂力（$f^*$的）上的$\ln r_f$（$r_f$是加载速率）的依赖性表现出两个不同的线性制度。第一种，在低$r_f$下，具有浅的斜率，而在高$r_f$下的斜率大得多，特别是对于LFA-1/ICAM-1复合物，两者之间的过渡发生在窄的$r_f$范围内。从模拟中提取的两个过渡态（TS）的位置显示出从低$r_f$或$F$的高值到高$r_f$或$F$的低值的突变。在其他蛋白质复合物的强迫断裂中，没有发现CAC从一种脆性（TS位置在一定的力范围内是恒定的）状态转换到另一种脆性状态的不寻常行为。我们解释这种新颖的行为，通过构建的自由能分布，$F(Λ)$的，作为一个集体反应坐标（$Λ$）的函数，涉及许多关键的带电残基和一个关键的金属离子。F（$Λ）中的TS位置在临界力处突然改变，表明它而不是分子延伸是良好的反应坐标。我们揭示了一个新的机制，在断裂动力学中观察到的两个加载机制。
英文摘要：
Cell adhesion complexes (CACs), which are activated by ligand binding, play key roles in many cellular functions ranging from cell cycle regulation to mediation of cell extracellular matrix adhesion. Inspired by single molecule pulling experiments on leukocyte function-associated antigen-1 (LFA-1), expressed in T-cells, bound to intercellular adhesion molecules (ICAM), we performed constant loading rate ($r_f$) and constant force ($F$) simulations using the Self-Organized Polymer (SOP) model to describe the mechanism of ligand rupture from CACs. The simulations reproduce the major experimental finding on the kinetics of the rupture process, namely, the dependence of the most probable rupture forces ($f^*$s) on $\ln r_f$ ($r_f$ is the loading rate) exhibits two distinct linear regimes. The first, at low $r_f$, has a shallow slope whereas the slope at high $r_f$ is much larger, especially for LFA-1/ICAM-1 complex with the transition between the two occurring over a narrow $r_f$ range. Locations of the two transition states (TSs), extracted from the simulations show an abrupt change from a high value at low $r_f$ or $F$ to a low value at high $r_f$ or $F$. The unusual behavior in which the CACs switch from one brittle (TS position is a constant over a range of forces) state to another brittle state is not found in forced-rupture in other protein complexes. We explain this novel behavior by constructing the free energy profiles, $F(Λ)$s, as a function of a collective reaction coordinate ($Λ$), involving many key charged residues and a critical metal ion. The TS positions in F($Λ) change abruptly at a critical force, demonstrating that it, rather than the molecular extension is a good reaction coordinate. We reveal a new mechanism for the two loading regimes observed in the rupture kinetics in CACs.
机构、总结、中文摘要均由AI分析而来，可能存在错误，请以论文正文为准。
