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

描述（由申请人提供）：提议的假设是，即使在低分辨率下，我们也可以找到并识别出正确的结构模型，该模型结合了良好的全原子填充和宽松的局部构象，从而具有高分辨率结构解的准确性。需要解决的问题是，生物学上重要的蛋白质和核酸大复合体只能以低分辨率（3¿或更低）产生衍射数据，其中原子间接触的功能关键细节不能直接看到，甚至整体折叠模式也变得不确定。我们在更高分辨率下成功开发和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，这项建议的重点是为这项任务制定和测试搜索程序，并确定解决方案的唯一性。这些想法与标准范例相矛盾，他们提出即使在低分辨率下也可以有效地利用晶体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特性兼容，因此即使在低分辨率下也可以实现详细的精度。公共卫生相关性：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的突破口，也是在原子水平上真正理解生物机制的突破口。如果这项研究成功的话，将把这个关键的转折点转移到更大的结构和复合体上，这是细胞生物学的真正机制，也是分子医学的关键应用点。

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.