Theory and simulation of protein dynamics, folding, and function

我们在与蛋白质动力学、折叠、结合和功能相关的几个领域取得了重大进展。通过原子模拟和实验相结合，我们能够确定结合到底物上的钙调神经磷酸酶的第一结构。这项工作是与教授小组合作进行的。Peti和Page(布朗大学)和Martha Cyert教授(斯坦福)。这种结构使我们更好地了解了调节这一重要信号蛋白的机制，以及参与免疫抑制的分子机制。我们还对ESCRT机制的功能有了新的认识。ESCRT蛋白是膜蛋白运输和其他细胞过程中的主要参与者，并被病毒，特别是艾滋病毒劫持。通过使用弹性膜模型，我们可以确定ESCRT诱导的囊泡形成的能量和动力学上可行的机制作为ESCRT功能的关键步骤。在与NIH Anfinrud博士的合作下，我们还可以确定光激活蛋白质PYP的早期中间结构和结构动力学。这项工作将时间分辨x射线结晶学与量子化学计算相结合。我们还在蛋白质-蛋白质相互作用网络的表征方面取得了重大进展。我们引入了界面交互网络，以建立交互网络的更详细和更具结构信息性的视图。在此基础上，我们可以提供证据，证明进化压力作用于相互作用网络的拓扑，以抑制来自非特定相互作用的竞争。

We have made significant progress in several areas related to protein dynamics, folding, binding, and function. By combining atomistic simulations and experiments, we are able to determine a first structure of calcineurin bound to a substrate. This work was carried out in collaboration with the groups of Profs. Peti and Page (Brown University) and Prof. Martha Cyert (Stanford). The structure provides us with a better understanding of the mechanisms used to regulate this important signalling protein, and of the molecular mechanisms involved in immunosuppression. We also gained new insight into the function of the ESCRT machinery. ESCRT proteins are a major player in membrane protein trafficking and other cellular processes, and are hijacked by viruses, in particular HIV. By using a an elastic membrane model we could determine an energetically and kinetically viable mechanism of ESCRT-induced vesicle formation as a key step in ESCRT function. In collaboration with the group of Dr. Anfinrud at the NIH, we could also determine early intermediate structures and the structural dynamics of the photoactivated protein PYP. This work combined time-resolved x-ray crystallography with quantum chemical calculations. We also made significant progress in the characterization of protein-protein interaction networks. We introduced the interface interactions network to establish a more detailed and structurally informative view of the interaction network. On this basis, we could provide evidence for evolutionary pressure acting on the topology of the interaction network to suppress competition from non-specific interactions.