Harnessing simulations to uncover molecular mechanisms of mechanosensing

项目摘要 为了执行一些最重要的功能，细胞必须能够产生、感知和 对机械力做出反应。已经发现了许多“机械感应”蛋白质，它们是 据信，在机械张力下，它们的行为会以可预测和可重复的方式改变。 然而，在大多数情况下，我们不知道这种力是如何改变 蛋白质所采用的构象，或者这如何导致伴随的功能变化。这个 机械传感的分子基础原则上可以用分子模拟来预测。 技术，然而，这种方法要么没有被采用，要么没有成功，因为 所涉及的力的大小很小，而机械传感器的尺寸和复杂性很大。在……里面 在这项工作中，我们将开发一套新的模拟方法来适当地采样蛋白质 构象和蛋白质配体在一系列小作用力下的寿命。我们将使用这些 在三种不同的环境中研究机械感觉的技术，我们认为三种不同的 采用了响应于力而改变行为的机制。总体而言，这些方面的工作 研究将使人们更好地理解细胞用来调节 它们在响应机械刺激时的行为，并扩展我们的模拟工具箱以能够 适当地抽样和评估他们对生理上很小的力量的反应。

Project Summary In order to perform some of their most important functions, cells must be able to generate, sense, and respond to mechanical forces. Many “mechanosensing” proteins have been discovered that are believed to change their behavior in a predictable and repeatable way when under mechanical tension. Yet, in most of these cases, we don’t know the molecular basis of how this force shifts the conformations adopted by the protein, or how this then leads to a concomitant change function. The molecular basis of mechanosensing can in principle be predicted using molecular simulation techniques, however this approach has either not been employed or not been successful because of the small magnitude of forces involved and the large size and complexity of the mechanosensors. In this work, we will develop a set of new simulation methodologies to properly sample protein conformations and protein-ligand biding lifetimes at a range of small forces. We will employ these techniques to study mechanosensing in three different contexts where we believe three distinct mechanisms for changing behavior in response to force are employed. Overall, the work in these studies will lead to a much greater understanding of the molecular paradigms used by cells to regulate their behavior in response to mechanical stimuli, and expand our simulation toolbox to be able to properly sample and assess their response to physiologically small forces.