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

“低分辨率室内

• 批准号: 7902302
• 负责人: JANE Shelby RICHARDSON
• 金额: $ 30.51万
• 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/7902302
• 关键词: Biological; Cellular biology; Complex; Data; Diagnosis; Drug Design; Hydrogen; Methods; Modeling; Molecular; Molecular Conformation; Molecular Medicine; Nucleic Acids; Pattern; Procedures; Property; Research; Resolution; Solutions; Structure; Testing; base; density; macromolecule; protein complex; public health relevance

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(由申请人提供)：建议的假设是，即使在低分辨率下，我们也可以找到并识别正确的结构模型，该模型将良好的全原子堆积与松弛的局部构象相结合，从而具有高分辨率结构解的精度。需要解决的问题是，具有生物重要性的蛋白质和核酸的大型复合体只能产生低分辨率(3？或更低)的衍射数据，在这种情况下，无法直接看到原子间接触的功能关键细节，甚至整个折叠模式也变得不确定。我们开发并在较高分辨率下成功应用的诊断和校正方法非常敏感，可以识别具有高分辨率有效性的模型，并基本上拒绝任何与此不正确的偏离。然而，识别这样的模型是一个非常困难且目前尚未解决的搜索问题。因此，这项提议的主旨是为这项任务制定和测试搜索程序，并确定解决办法的独特性。这些想法与标准范式相矛盾，提出了即使在低分辨率下也可以有效地利用结晶学上看不见的氢原子，只有一小部分模型与密度和已知的分子性质兼容，因此即使在低分辨率下实际上也可能实现详细的准确性。与公共健康相关：大分子的高分辨率结构模型是合理的、基于结构的药物设计以及在原子水平上真正理解生物机制的突破口。这项拟议的研究如果成功，将把这一关键转折点转移到更大的结构和复合体上，这些结构和复合体是细胞生物学的真正机械，也是分子医学的关键应用点。