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

化学学部的有机和大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Nikolai Strynnikov教授和德国莱布尼茨分子药理学研究所的Bernd Reif教授的合作研究项目。该奖项与德国研究协会（DFG）资助的合作奖相协调。该合作旨在比较并最终结合溶液和固态核磁共振实验的动态数据。大量证据表明，许多形式的内部运动在从溶液过渡到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表现出类似的动态行为。另一方面，光谱学的背景是不同的：固体数据对皮秒（ps）到纳秒（ns）时间框架内的内部动力学非常敏感，而溶液弛豫率只对那些比分子翻滚更快的运动敏感。两种互补的光谱视角的结合可以为蛋白质动力学提供独特的见解。这项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。在固体和溶液中，甲基的自旋-晶格弛豫是由内部动力学（快速甲基自旋）控制的。因此，这种类型的数据提供了在两个样本之间进行直接比较的方便机会。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。具体来说，骨干15N弛豫数据将通过同时拟合溶液弛豫率和固态弛豫率以组合方式进行分析。预计皮秒和纳秒动力学的分离可以沿着这些路线实现，从而在描述蛋白质运动时达到一个新的细节水平。相似范式可以扩展到许多核磁共振实验和一般生物物理意义的蛋白质系统。化学学部的有机和大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支持普渡大学的Nikolai Strynnikov教授和德国莱布尼茨分子药理学研究所的Bernd Reif教授之间的联合合作，他们将采用溶液和固态核磁共振来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潜在的影响。由此产生的进展可以促进从静态到动态蛋白质模型的典型应用，如合理的药物设计和生物技术的过渡。美国和德国实验室之间的互访将拓宽参与的学生的科学视野。为了进一步增加学生对国际科学的接触，接收方将组织学生参观主要的国家研究机构。美国首席研究员将与德国PI一起在一年一度的欧洲暑期学校组织一次关于固态核磁共振的特别会议，专门讨论“固体与溶液相遇”的领域。一位在该领域做出重大贡献的年轻美国科学家（研究生或博士后水平）将被确定并有机会在本次会议上介绍他/她的工作。脉冲序列和编写的计算机程序将通过参与者的网站提供给广泛的核磁共振社区。

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.