"Low-Resolution Interiors & Interfaces Can Achieve High-Resolution Accuracy"

“低分辨率室内

• 批准号: 8114979
• 负责人: JANE Shelby RICHARDSON
• 金额: $ 30.21万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8114979
• 关键词: Biological; Cellular biology; Complex; Data; Diagnosis; Drug Design; Health; Hydrogen; Methods; Modeling; Molecular; Molecular Conformation; Molecular Medicine; Nucleic Acids; Pattern; Procedures; Property; Research; Resolution; Solutions; Structure; Testing; base; density; macromolecule; protein complex

DESCRIPTION (provided by applicant): The proposal hypothesis is that even at low resolution, we can find and identify the correct structure model that combines good all-atom packing with relaxed local conformations and thus has the accuracy of a high- resolution structure solution. The problem to be solved is that biologically important large complexes of proteins and nucleic acids yield diffraction data only to low resolution (3¿ or worse), where functionally critical details of interatomic contacts cannot be seen directly and even overall folding patterns become uncertain. The diagnosis and correction methods we developed and applied successfully at higher resolution are extremely sensitive and can recognize a model with high-resolution validity and reject essentially any incorrect departure from that. However, it is a very difficult and currently unsolved search problem to identify such a model. The thrust of this proposal is therefore to develop and test search procedures for this task and determine the uniqueness of the solutions. These ideas contradict the standard paradigm by proposing that the crystallographically invisible hydrogen atoms can be effectively used even at low resolution, that only a small range of models are compatible both with the density and with known molecular properties, and therefore that detailed accuracy might actually be attainable even at low resolution. PUBLIC HEALTH RELEVANCE: High-resolution structure models of macromolecules are the breakthrough place for rational, structure- based drug design, as well as for truly understanding biological mechanisms at the atomic level. The proposed research if successful will move that critical tipping point out to larger structures and complexes which are the real machinery of cellular biology and a key application point for molecular medicine.

描述（由适用提供）：提案假设是，即使在低分辨率下，我们也可以找到并确定将良好的全原子包装与放松的局部组成结合在一起的正确结构模型，因此具有高分辨率结构解决方案的准确性。要解决的问题是，生物学上重要的蛋白质和核酸的大复合物仅产生衍射数据，仅能直接看到原子间接触的功能关键细节，即使整体折叠模式在功能上进行关键的细节也变得不确定。我们在较高分辨率下成功开发和应用的诊断和校正方法非常敏感，并且可以识别具有高分辨率有效性的模型，并且拒绝与此相关的任何错误出发。但是，识别这种模型是一个非常困难的搜索问题。因此，该提案的目的是为此任务开发和测试搜索程序，并确定解决方案的唯一性。这些想法通过提出即使在低分辨率下也可以有效地使用晶体上看不见的氢原子来与标准范式相矛盾，只有一小部分模型与密度和已知的分子特性都兼容，因此即使在低分辨率下，详细的精度实际上也可以可用。公共卫生相关性：大分子的高分辨率结构模型是理性，基于结构的药物设计的突破性，以及真正了解原子水平的生物学机制。拟议的研究如果成功将把关键的倾斜指出指向更大的结构和复合物，这些结构和复合物是细胞生物学的真正机制，也是分子医学的关键应用点。