MOLECULAR SIMULATIONS OF INTEGRIN CONFORMATIONAL CHANGE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 整合素是介导细胞-细胞、细胞-细胞外基质和细胞-病原体相互作用的黏附分子，通过整合细胞外环境中的细胞骨架和贴附点来调节抗力黏附、极化反应和细胞迁移。它们对人类和许多其他生物至关重要，因为它们与重要的生理过程有关，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。整合素分子是具有非共价结合的a-和b-亚基的杂二聚体。在脊椎动物中已经报道了19个不同的a-亚基和8个不同的b-亚基，形成了至少25个ab异源二聚体。整合素参与双向信号传递过程。它们通常处于非活性状态，在这种状态下，它们以低亲和力结合配体，不发出信号，需要被激活才能发挥作用。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。提出了一个开关叶片模型来解释整合素的构象变化。然而，通过实验观察整合素的构象变化过程是困难的。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.