Integrated approach to protein dynamics: bringing together solid- and solution-state NMR data

蛋白质动力学的综合方法：汇集固态和溶液态 NMR 数据

• 批准号: 0723718
• 负责人: Nikolai Skrynnikov
• 金额: $ 37.5万
• 依托单位: Purdue University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0723718&HistoricalAwards=false
• 关键词: Integrated; approach; protein; dynamics; bringing

The Organic and Macromolecular Chemistry Program in the Division of Chemistry and the Europe and Eurasia Program in the Office of International Science and Engineering will support the collaborative research program of Professors Nikolai Strynnikov of Purdue University and Bernd Reif of the Leibniz-Institute for Molecular Pharmacology in Germany. This award coordinates with a collaborative award funded by the Deutsche Forschungsgemeinschaft (DFG). The collaboration seeks to compare and ultimately combine the dynamics data from solution- and solid-state NMR experiments. Substantial evidence exists that many forms of internal motion do not change significantly upon transition from solution to solid ('similarity hypothesis'). For instance, side chains sequestered in the protein hydrophobic core are likely to show similar dynamic behavior. The spectroscopic context, on the other hand, is different: solid data are broadly sensitive to internal dynamics in the picoseconds (ps) to nanoseconds (ns) time frame, whereas the solution relaxation rates are sensitive only to those motions that are faster than molecular tumbling. The combination of the two complementary spectroscopic perspectives can provide a unique insight into protein dynamics. The research will follow a two-step scheme. First, the investigators are planning to focus on side-chain methyl groups. Spin-lattice relaxation in methyls is dominated by the internal dynamics (fast methyl spinning) in solids and solutions alike. This type of data offers, therefore, a convenient opportunity to draw a direct comparison between the two samples. Based on the methyl data, the investigators plan to establish support for their 'similarity hypothesis'. In the second stage of the project, the benefits of the similarity will be exploited. Specifically, backbone 15N relaxation data will be analyzed in a combined fashion by fitting simultaneously the solution- and solid-state relaxation rates. It is anticipated that a separation of the picosecond and nanosecond dynamics can be achieved along these lines, leading to a new level of detail in the description of protein motions. The similarity paradigm can be extended to many NMR experiments and to protein systems of general biophysical significance.The Organic and Macromolecular Chemistry Program in the Division of Chemistry and the Europe and Eurasia Program in the Office of International Science and Engineering support the joint collaboration between Professors Nikolai Strynnikov of Purdue University and Bernd Reif of the Leibniz-Institute for Molecular Pharmacology in Germany who will employ solution- and solid-state NMR to study biomolecular dynamics. The integration of the two approaches can potentially have an impact across the entire field of protein science. The resulting progress can facilitate the transition from static to dynamic protein models in quintessential applications such as rational drug design and biotechnology. The exchange visits between the US and the German laboratories will broaden the scientific horizons of the students involved. To further increase the students' exposure to international science, visits to the leading national research institutions will be organized by the receiving side. The US principal investigator will join the German PI to organize a special session at the annual European Summer School on solid-state NMR dedicated to the area 'where solid meets solution'. One young US scientist (at the graduate student or postdoctoral level) who made a significant contribution in this area will be identified and given an opportunity to present his/her work at this meeting. The pulse sequences and computer programs written as a result of the proposed research will be made available to the broad NMR community through the participants' websites.

化学系的有机和高分子化学项目以及国际科学与工程办公室的欧洲和欧亚项目将支持普渡大学的尼古拉·斯特林尼科夫教授和德国莱布尼茨分子药理学研究所的贝恩德·赖夫教授的合作研究项目。该奖项与由德国研究共同体（DFG）资助的合作奖协调。该合作旨在比较并最终联合收割机的动态数据从溶液和固态核磁共振实验。大量证据表明，许多形式的内部运动在从溶液转变为固体时不会发生显着变化（“相似性假设”）。例如，隔离在蛋白质疏水核心中的侧链可能显示出类似的动力学行为。另一方面，光谱背景是不同的：固体数据在皮秒（ps）到纳秒（ns）的时间范围内对内部动力学广泛敏感，而溶液弛豫速率只对那些比分子翻滚更快的运动敏感。这两种互补的光谱学观点的结合可以提供对蛋白质动力学的独特见解。该研究将遵循两步计划。首先，研究人员计划将重点放在侧链甲基上。甲基的自旋-晶格弛豫由固体和溶液中的内部动力学（快速甲基自旋）主导。因此，这类数据为直接比较两个样本提供了便利的机会。基于甲基数据，研究人员计划为他们的“相似性假设”建立支持。在项目的第二阶段，将利用相似性的好处。具体而言，骨干15 N弛豫数据将进行分析，在一个组合的方式，同时拟合的解决方案和固态弛豫速率。可以预期的是，皮秒和纳秒动力学的分离可以实现沿着这些线，导致一个新的水平的详细描述的蛋白质运动。相似性范例可以扩展到许多NMR实验和一般生物物理意义的蛋白质系统。化学系的有机和大分子化学计划以及国际科学与工程办公室的欧洲和欧亚计划支持普渡大学的Nikolai Strynnikov教授和Leibniz的Bernd Reif教授之间的联合合作。德国的分子药理学研究所，他将利用溶液和固态核磁共振研究生物分子动力学。这两种方法的整合可能会对整个蛋白质科学领域产生影响。由此产生的进展可以促进合理药物设计和生物技术等典型应用中从静态蛋白质模型到动态蛋白质模型的转变。美国和德国实验室之间的交流访问将拓宽相关学生的科学视野。为了进一步增加学生对国际科学的接触，接收方将组织对领先的国家研究机构的访问。美国首席研究员将与德国PI一起在年度欧洲暑期学校组织一次关于固态NMR的特别会议，致力于“固体与溶液相遇”的领域。将确定一名在这一领域作出重大贡献的年轻美国科学家（研究生或博士后），并给予机会在本次会议上介绍其工作。作为拟议研究结果编写的脉冲序列和计算机程序将通过参与者的网站提供给广大的NMR社区。