Structural Dynamics at LCLS

摘要：推动生物医学项目组合 在拟议的BTRR的这一组成部分中选择了九个驱动生物医学项目（DBP）。 选择这些消毒副产物是基于高科学价值以及它们对X射线方法的需要 以获得结构和动态信息，揭示各种结构的详细功能， 感兴趣的生物分子。因此，它们实现了提供科学背景的主要目的 以及拟议的BTRR开发技术的动机。DBPs还将 为开发的技术提供必要的测试平台，并创造一个良性循环的迭代 技术发展，将导致新的广泛可用的能力，为生物医学 社区 DBPs按照沿着三个主题组织。1-大分子结构测定 和膜蛋白。2-准确测定了化合物的活性中心结构， 金属酶，如核糖核苷酸还原酶和细胞色素c氧化酶，以及复合物 大分子机器，如RNA聚合酶-II。3-所有DBPs的共同研究领域 涉及时间分辨（TR）研究，包括研究以下动态过程， 腺嘌呤核糖开关信号，N.淋病MtrF，抗生素结合 和CypA变体的相互作用特异性的检查。 这些DBP将推动使用直线加速器进行高效结构测定的方法开发 相干光源（LCLS）。它们还将推动稳健快速混合的发展 将揭示抗生素结合动力学或具有高空间分辨率的酶促反应的能力 以及光激活笼状化合物释放的新方法， 了解生物分子中的构象空间动力学，利用光将它们推出 均衡 总的来说，拟议的DBPs涵盖了广泛的科学问题，这些问题对 生物医学界和NIH，他们代表了一套强大的要求，将推动 将BTRR技术转变为将长期服务于生物医学界的工具。

ABSTRACT: DRIVING BIOMEDICAL PROJECTS PORTFOLIO Nine Driving Biomedical Projects (DBP) are selected in this component of the proposed BTRR. These DBPs were selected based on high scientific merit as well as their need for X-ray methods to obtain structural and dynamic information that will reveal the detailed function of various biomolecules of interest. As such, they fulfil the primary purpose of providing scientific context and motivation for the technologies to be developed by the proposed BTRR. The DBPs will also provide necessary test beds for the developed technologies and create a virtuous cycle of iterative technology development that will lead to new broadly available capabilities for the biomedical community. The DBPs are organized along three themes. 1-Structure determination of large macromolecules and membrane proteins. 2-The determination of accurate active site structures of metalloenzymes, such as ribonucleotide reductase and cytochrome c oxidase, and complex macromolecular machines, such as RNA polymerase-II. 3-A common research area of all DBPs involve time-resolved (TR) studies that include research to follow dynamic processes involved in adenine riboswitch signaling, the transport mechanism of N. gonorrhoeae MtrF, antibiotic binding to β-lactamase and examination of interaction specificity of CypA variants. These DBPs will drive method developments in efficient structure determination using the Linac Coherent Light Source (LCLS). They will also drive the development of robust rapid mixing capabilities that will reveal antibiotic binding dynamics or enzymatic reactions with high spatial and temporal resolution, as well as new methods in light activated caged compound release and understanding conformational space dynamics in biomolecules using light to push them out of equilibrium. Overall, the proposed DBPs cover a breadth of scientific problems of high interest to the biomedical community and NIH and they represent a strong set of requirements that will push the BTRR technologies towards tools that will serve the biomedical community for the long term.