MOLECULAR SIMULATIONS OF INTEGRIN CONFORMATIONAL CHANGE

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者的研究机构。 整合素是介导细胞-细胞、细胞-细胞外基质和细胞-病原体相互作用的粘附分子，其可以通过将细胞骨架与细胞外环境中的附着点整合来调节抵抗力粘附、响应于细胞外线索的极化和细胞迁移。它们对人类和许多其他生物体至关重要，因为它们与重要的生理过程如组织形态发生、炎症、伤口愈合以及细胞生长和分化的调节有关。整联蛋白分子是具有非共价缔合的a亚基和b亚基的异二聚体。在脊椎动物中已经报道了19种不同的a亚基和8种不同的b亚基，形成至少25种ab异二聚体。整合素参与双向信号传导过程。它们通常处于非活性状态，其中它们以低亲和力结合配体并且不发出信号，并且需要被激活以发挥功能。根据实验数据，研究人员认为整合素具有多种构象，整合素的激活是通过其从弯曲到延伸的构象变化来完成的。提出了一个弹簧刀模型来解释整合素的构象变化。然而，通过实验很难观察到整合素构象变化的过程。在这里，我们建议使用分子动力学模拟来揭示整合素构象变化的途径，从而揭示整合素激活的结构基础。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Integrins, which are adhesion molecules mediating cell-cell, cell-extracellular matrix, and cell-pathogen interactions, can regulate force-resistant adhesion, polarization in response to extracellular cues, and cell migration by integrating the cytoskeleton of cells with points of attachment in extracellular environments. They are of vital importance to humans and many other organisms because they are related to important physiological processes such as tissue morphogenesis, inflammation, wound healing, and the regulation of cell growth and differentiation. An integrin molecule is a heterodimer with noncovalently associated a- and b-subunits. Nineteen different a-subunits and eight different b-subunits have been reported in vertebrates, forming at least twenty-five ab heterodimers. Integrins are involved in bi-directional signaling processes. They are often in an inactive state in which they bind ligands with low affinity and do not signal, and need to be activated in order to function. According to experimental data, researchers suggest that integrins have multiple conformations and the activation of integrins is accomplished by their conformational change from the bent to the extended. A switch-blade model was provided to explain the conformational change of integrins. However, it is difficult to observe the process of integrin conformational change by experiments. Here, we propose to use molecular dynamics simulations to uncover the pathway of integrin conformational change, and therefore, reveal the structural basis underline integrin activation.