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Life under tension: Computational studies of proteins involved in mechanotransduction.

机译：紧张生活：涉及机械转导的蛋白质的计算研究。

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Living organisms rely on macroscopic and microscopic structures that produce and transform force: from mechanical motion of our muscles and bones to sound transduction and cell volume regulation, handling of forces is essential to life. Investigation of the microscopic machinery behind force generation and transduction in the cell has only become possible with recent advances in x-ray crystallography, nuclear magnetic resonance spectroscopy, single-molecule force spectroscopy, and computer modeling. In this thesis, molecular dynamics simulations have been used to study proteins that transform forces into biochemical signals (mechanotransduction). The first protein studied is the mechanosensitive channel of small conductance MscS. This membrane channel has been proposed to act as a safety valve during osmotic shock, facilitating the release of ions and small solutes upon increase in membrane tension, thereby preventing bacterial cells from bursting. The second set of proteins studied are ankyrin and cadherin repeats, likely forming part of the transduction apparatus in hearing and other mechanical senses. Simulations of all these proteins went beyond the standard approach in which only equilibrium properties are monitored; we adopted and developed strategies in which external electric fields and forces are used to probe their response and function and at the same time produce verifiable predictions. The outcome of the simulations performed on MscS, in close collaborations with experimentalists, allowed us to establish conduction properties of different conformations and propose structural models of MscS's open and closed states. Simulations of ankyrin and cadherin repeats focused on their elastic properties, resulting in the discovery and prediction of ankyrin's tertiary and secondary structure elasticity (later on corroborated by atomic force microscopy experiments), and the discovery of a novel form of secondary structure elasticity mediated by calcium ions in cadherins. Simulations also revealed how calcium ions control cadherin's shape and the availability of key residues involved in cell-cell adhesion, suggesting a conceptual framework for interpreting mutations in cadherin calcium binding motifs causing hereditary deafness. Overall, simulations provided a unique nanoscopic view of the dynamics and function of some of the proteins involved in mechanotransduction.
机译：生命有机体依赖于产生和转化力的宏观和微观结构：从我们的肌肉和骨骼的机械运动到声音的传导和细胞体积调节，力的处理对于生命至关重要。随着X射线晶体学，核磁共振波谱，单分子力波谱和计算机建模的最新进展，研究细胞内力产生和传递的微观机制才成为可能。在本文中，分子动力学模拟已用于研究将力转化为生化信号（机械转导）的蛋白质。研究的第一个蛋白质是小电导MscS的机械敏感通道。已经提出该膜通道在渗透性休克期间用作安全阀，当膜张力增加时促进离子和小溶质的释放，从而防止细菌细胞破裂。研究的第二组蛋白质是锚蛋白和钙黏着蛋白重复序列​​，在听力和其他机械意义上可能构成转导设备的一部分。对所有这些蛋白质的模拟超出了仅监测平衡特性的标准方法。我们采用并开发了使用外部电场和力来探测其响应和功能并同时产生可验证的预测的策略。在MscS上进行的仿真结果与实验人员紧密合作，使我们能够建立不同构型的传导特性，并提出MscS的打开和关闭状态的结构模型。锚蛋白和钙粘蛋白重复序列​​的模拟主要集中在它们的弹性特性上，从而发现和预测了锚蛋白的三级和二级结构弹性（后来被原子力显微镜实验所证实），并发现了钙介导的新型形式的二级结构弹性钙离子中的离子。模拟还揭示了钙离子如何控制钙黏着蛋白的形状以及参与细胞粘附的关键残基的可用性，为解释钙黏着蛋白钙结合基序突变引起的遗传性耳聋提供了概念框架。总体而言，模拟为涉及机械转导的某些蛋白质的动力学和功能提供了独特的纳米视角。

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