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

本提案描述了生物医学技术开发的使命和战略计划， 传播中心（RM 1），名称为核磁共振波谱法大分子动力学中心 (CoMD/NMR）。位于纽约结构生物学中心的CoMD/NMR开发了新的 NMR光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。在这里，我们主要关注自旋弛豫方法， 已经对表征生物学过程中蛋白质和核酸构象动力学产生了巨大的影响 过程包括配体识别、变构、寡聚化、催化和折叠。中央 CoMD/NMR解决的一个挑战是打破新用户申请的高激活障碍 先进的NMR光谱和计算方法，从而使复杂的NMR方法 提供给广泛的生物研究社区。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欠定的，我们开发了新的 实验，脉冲序列和计算方法。 (ii)由于对许多用户来说，使用先进的核磁共振仪器可能是一个限制，我们提供了访问 到一系列使NMR仪器，包括NMR光谱仪在多个静态磁 场，一系列现代探针，动态核极化，快速冷冻淬火，高压 设备，和现场循环松弛，所有在一个维护良好，工作人员支持，多用户 环境 (iii)因为技术转移到生物学家（甚至核磁共振光谱学家）受到了阻碍， 方法的复杂性，以及由于工具的时间有效使用至关重要，我们开发了 强大高效的管道，以促进实验规划，数据采集和分析， 专家。 (iv)因为生物学家的研究项目，将受益于这些方法是不知道的， 潜力，我们从事社区外展和教育。 我们计划的一个独特优势是最前沿的固态NMR，溶液NMR和 计算专家，这项建议强调了这些方法的协同作用。此外，作为 位于NYSBC内，我们与X射线衍射，Cryo EM和膜 蛋白质生产技术。鉴于这三个技术开发项目的要求很高， （TDPs），我们已经确定了一些技术伙伴计划（TPP）， 在核磁共振方面的世界领导者表示他们渴望与我们合作。技术 当由令人兴奋和具有挑战性的应用驱动时，开发进行得最有效;因此， CoMD/NMR将通过协作和合作与优秀的当地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， 包括广泛的培训和宣传方案。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.