Structural Dynamics at LCLS

摘要：推动生物医学项目组合 在拟议的BTRR的这一部分中，选择了九个驱动生物医学项目(DBP)。 这些DBP是基于很高的科学价值以及他们对X射线方法的需求而选择的 以获取结构和动态信息，以揭示各种 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将开发的技术的动机。DBP还将 为开发的技术提供必要的测试平台，并创建迭代的良性循环 将为生物医学带来新的广泛可用的能力的技术开发 社区。 DBP围绕三个主题组织。大分子的1-结构测定 和膜蛋白。2-准确的活性中心结构的测定 金属酶，如核糖核苷酸还原酶和细胞色素C氧化酶，以及复合体 大分子机器，如RNA聚合酶-II。3-所有DBP的共同研究领域 涉及时间分辨(Tr)研究，包括跟踪涉及的动态过程的研究 腺嘌呤核糖开关信号、淋球菌mtrF转运机制、抗生素结合 对β-内酰胺酶及CypA变异体相互作用特异性的检测。 这些DBP将推动使用直线加速器进行有效结构确定的方法开发 相干光源(LCLS)。它们还将推动强健快速混合的发展 揭示抗生素结合动力学或高空间酶反应的能力 和时间分辨率，以及光活化笼状化合物释放和释放的新方法 用光推动生物分子的构象空间动力学 均衡。 总体而言，拟议的DBP涵盖了广泛的科学问题，这些问题是 生物医学界和NIH，他们代表了一套强有力的要求，将推动 将BTRR技术转化为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.