Multi-scale molecular simulations and artificial design of long-range conformational switches (B12*)

长程构象转变调节分子伴侣、离子泵、酶和信号蛋白的活性，但这种远距离作用的机制原理尚不清楚。在这个项目中，我们使用多尺度量子和经典分子模拟技术来提供对远程构象蛋白质开关的结构、功能和动力学的分子洞察。我们将研究热休克蛋白(HSP)90的机制，分子模拟是与CRC内的实验小组密切合作进行的。我们的目标是阐明翻译后修饰、效应器分子结合和蛋白质二聚是如何干扰催化活性的。为了研究一般的长程耦合原理，我们在人工螺旋束蛋白质中设计了分子开关，最终目标是设计一种静电开关，它可以通过束内带电残基阵列的构象变化来调节远距离的ATPase活性。

Long-range conformational transitions modulate the activity of molecular chaperones, ion pumps, enzymes, and signalling proteins, but the mechanistic principles of this action-at-a-distance effect are poorly understood. In this project we employ multi-scale quantum and classical molecular simulation techniques to provide molecular insight into the structure, function, and dynamics of long-range conformational protein switches. We will study the heat shock protein (Hsp) 90 machinery, for which the molecular simulations are performed in close collaboration with the experimental groups within the CRC. We aim to elucidate how post-translation modifications, effector molecule binding, and protein dimerisation perturb the catalytic activity. To study the general long-range coupling principles, we design molecular switches in artificial helical bundle proteins, with an ultimate goal to design an electrostatic switch that can modulate an ATPase activity at large distances by conformational changes in arrays of charged residues within the bundle.