NMR and Computational Studies of Biomolecules

拟议研究的总体目标是开发和 应用方法表征大的蛋白质和蛋白质与其他大分子或蛋白质的络合物 小配体。这具有很高的意义，因为蛋白质相互作用是许多生物的关键 这一过程可能是与人类疾病作斗争的治疗干预措施的切入点。计划中的 研究将包括核磁共振、计算和生化方法。核磁共振方法将大举入库 关于非均匀抽样方法，这是由本P0-1开创的，并已显示 为了显著提高与分辨率匹配的多维核磁共振实验的分辨率 可以用现代的核磁共振硬件来实现。特别感兴趣的将是弱交互的重点 难以结晶的蛋白质复合体，不能很好地分辨核磁共振谱，并表现出 当用标准方法研究时，严重的线条加宽。因此，P0-1将处理一个严重的 只有用新的核磁共振方法才能解决的结构生物学问题。建议数 研究包括五个研究组成部分和三个核心。组件1(瓦格纳)将开发 大分子蛋白质和蛋白质结构研究的实验和计算方法 复合体。组件2(Wagner)提出了组合计算的发展和应用 以及蛋白质与小分子和其他大分子相互作用的实验方法 适用于实验约束稀疏的情况。构成部分3(Hoch)建议进一步 开发和应用蛋白质光谱的非均匀采样和非均匀采样的处理方法 获取的数据。组件4(Walsh)针对的是 非核糖体多肽合成酶Entf和EntB。总体目标是理解 细菌产生不寻常多肽的机制，其中一些具有重要的药理作用 属性。组件5(周)专注于基于DNA的新比对介质的开发 用于测量剩余偶极耦合和获得定义蛋白质的新限制的策略 在水溶液和洗涤剂胶束中的络合物。这项研究将得到三个方面的支持 管理核心(核心A)、核磁共振仪器(核心B)和计算核心(核心C)。这个P0-1 已经并将对该地区的生物科学产生广泛影响。它刺激了无数人 与其他生物学家的合作，并产生了许多受益于专业知识的出版物 在这笔赠款中开发的。

The overall goal of the proposed research is to develop and apply methods for characterizing large proteins and protein complexes with other macromolecules or small ligands. This is of high significance since protein interactions are key to many biological processes and may be entry points for therapeutic interventions to fight human diseases. The planned research will include NMR, computational and biochemical approaches. NMR methods will heavily bank on non-uniform sampling approaches, which have been pioneered by this P0-1 and have been shown to dramatically extend the resolution of multidimensional NMR experiments matching the resolution achievable with modern NMR hardware. Of particular interest will be the focus on weakly interacting protein complexes that are difficult to crystallize, do not exhibit well-resolved NMR spectra and exhibit severe line broadening when studied with standard approaches. Thus, the P0-1 will tackle a serious problem of structural biology that can only be solved with new NMR approaches. The proposed research contains five research components and three cores. Component 1 (Wagner) will develop experimental and computational approaches for structural studies of large proteins and protein complexes. Component 2 (Wagner) proposes development and application of combined computational and experimental approaches for protein interactions with small molecules and other macromolecules for situations where experimental constraints are sparse. Component 3 (Hoch) proposes to further develop and apply methods for non-uniform sampling of protein spectra and processing of the nonuniformly acquired data. Component 4 (Walsh) targets structures and interactions of modules of the non-ribosomal polypeptide synthetases EntF and EntB. The overall goal is to understand the mechanisms by which bacteria make unusual peptides, some of which have important pharmacological properties. Component 5 (Chou) is focused on the development of new DNA-based alignment media for measuring residual dipolar couplings and strategies for obtaining new restraints for defining protein complexes both in aqueous solution and detergent micelles. The research will be supported by three cores for Administration (Core A), NMR instrumentation (Core B) and Computation (Core C). This P0-1 has had and will have a wide impact on biological science in the region. It stimulated numerous collaborations with other biologists and resulting in many publications that benefited from the expertise developed in this grant.