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， 对机械力作出反应。已经发现了许多“机械感应”蛋白， 相信在机械张力下以可预测和可重复的方式改变它们的行为。 然而，在大多数情况下，我们不知道这种力如何改变分子的基础。 蛋白质所采用的构象，或者这如何导致伴随的变化功能。的 机械传感的分子基础原则上可以使用分子模拟来预测 技术，然而，这种方法要么没有被采用，要么没有成功，因为 所涉及的力的幅度小以及机械传感器的尺寸大和复杂性。在 在这项工作中，我们将开发一套新的模拟方法来正确地采样蛋白质 在一系列小力下的构象和蛋白质-配体结合寿命。我们将利用这些 在三种不同的背景下研究机械传感的技术，我们相信其中有三种不同的 采用了响应于力而改变行为的机制。总的来说，这些工作 研究将导致对细胞调节的分子模式有更深入的了解， 他们对机械刺激的反应行为，并扩展我们的模拟工具箱， 适当取样并评估其对生理小力的反应。

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.