RM1 Center on Macromolecular Dynamics by NMR Spectroscopy at the New York Structural Biology Center (CoMD/NMR)

该提案描述了生物医学技术开发和发展的使命和战略计划 传播中心（RM1）题为核磁共振波谱大分子动力学中心 (CoMD/NMR)。位于纽约结构生物学中心的 CoMD/NMR 开发了新的 核磁共振波谱学的实验和计算技术，包括结构和动力学 溶液和固态 NMR 方法。这里我们主要关注自旋弛豫方法，其中有 已经对生物过程中蛋白质和核酸构象动力学的表征产生了巨大影响 过程包括配体识别、变构、寡聚、催化和折叠。中央 CoMD/NMR 解决的挑战是打破新用户申请的高激活障碍 先进的核磁共振波谱和计算方法，从而形成复杂的核磁共振方法 可供广泛的生物学研究界使用。为此，CoMD/NMR 解决了四个主要障碍。 (i) 由于生物聚合物的动力学问题经常是不确定的，我们开发了深刻的新方法 实验、脉冲序列和计算方法。 (ii) 由于访问高级 NMR 仪器对许多用户来说可能是一个限制，因此我们提供访问权限 一系列可用的 NMR 仪器，包括在多个静态磁场下的 NMR 波谱仪 场、一系列现代探针、动态核极化、快速冷冻淬火、高压 设备和野外自行车松弛测量仪，全部都在维护良好、工作人员支持和多用户的情况下 环境。 (iii) 因为技术向生物学家（甚至核磁共振波谱学家）的转让受到了阻碍 由于方法的复杂性，并且由于仪器的时间高效使用至关重要，我们开发了 强大高效的管道，以促进非实验规划、数据采集和分析 专家。 (iv) 因为拥有将从这些方法中受益的研究项目的生物学家不知道 潜力，我们参与社区外展和教育。 我们项目的独特优势是前沿固态 NMR、溶液 NMR 和 计算专家，该提案强调了这些方法之间的协同作用。此外，被 我们位于 NYSBC 内，与 X 射线衍射、冷冻电镜和膜有良好的合作伙伴关系 蛋白质生产技术。鉴于这三个技术开发项目的要求很高 (TDP) 在此提出，我们已经确定了许多技术合作伙伴项目 (TPP)， 核磁共振领域的世界领先者表示渴望与我们合作。技术 当由令人兴奋和具有挑战性的应用程序驱动时，开发进展最有效；因此， CoMD/NMR 将通过协作和合作与优秀的地方和国家研究人员密切合作 服务项目 (CSP)、推动生物医学项目 (DBB) 和社区参与 (CE) 活动， 包括广泛的培训和传播计划。通过其各种组件，CoMD/NMR 将 影响与人类健康相关的各种生物学研究，包括退行性疾病， 代谢紊乱和癌症。

This proposal describes the mission and strategic plans for of a Biomedical Technology Development and Dissemination Center (RM1) entitled Center on Macromolecular Dynamics by NMR Spectroscopy (CoMD/NMR). Located at the New York Structural Biology Center, CoMD/NMR has developed new experimental and computational techniques in NMR spectroscopy, including both structure and dynamics methods for both solution and solid state NMR. Here we focus mainly on spin relaxation methods, which have already had great impact for characterizing protein and nucleic acid conformational dynamics during biological processes including ligand recognition, allosterism, oligomerization, catalysis, and folding. The central challenge addressed by CoMD/NMR is to break down the high activation barrier for new users to apply advanced NMR spectroscopic and computational methods and thereby make sophisticated NMR approaches available to a wide biological research community. To do so, CoMD/NMR addresses four primary obstacles. (i) Because dynamics problems for biopolymers are frequently underdetermined, we develop incisive new experiments, pulse sequences and computational methods. (ii) Because access to advanced NMR instruments can be a limitation for many users, we provide access to a range of enabling NMR instrumentation, including NMR spectrometers at multiple static magnetic fields, a range of modern probes, dynamic nuclear polarization, rapid-freeze-quench, high-pressure equipment, and field cycling relaxometry, all in a well maintained, staff supported, and multiuser environment. (iii) Because transfer of technology to biologists (and even to NMR spectroscopists) has been hindered by the complexity of the methods, and since time efficient use of the instruments is crucial, we develop robust efficient pipelines to facilitate experimental planning, data acquisition and analysis by non- specialists. (iv) Because biologists with research programs that would benefit from these methods are unaware of the potential, we engage in community outreach and education. A unique strength of our program is the integration of forefront solid state NMR, solution NMR and computational experts, and this proposal highlights synergy across these approaches. Additionally, being situated within the NYSBC, we have excellent partnerships with X-ray diffraction, Cryo EM, and membrane protein production technologies. Given the demanding nature of the three Technology Development Projects (TDPs) proposed herein, we have identified a number of Technology Partnership Projects (TPPs), engaging world leaders in aspects of NMR who have indicated their eagerness to partner with us. Technology development proceeds most effectively when driven by exciting and challenging applications; accordingly, CoMD/NMR will work closely with outstanding local and national investigators through Collaborative and Service Projects (CSP), Driving Biomedical Projects (DBB) and Community Engagement (CE) activities, including extensive training and dissemination programs. Through its various components, CoMD/NMR will impact a diverse range of biological research with human health relatedness, including degenerative diseases, metabolic disorders, and cancer.