Ab Initio Phasing of Macromolecules

大分子从头开始定相

• 批准号: 7034099
• 负责人: ZBYSZEK OTWINOWSKI
• 金额: $ 22.13万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7034099
• 关键词: X ray crystallography; chemical structure; crystallization; electron density; macromolecule; method development; molecular asymmetry; structural biology

DESCRIPTION (provided by applicant): This grant is to solve ab initio the phase problem, a classic high risk/high impact challenge in structural biology. The macromolecular structure determination will be improved by novel approaches to identifying non-crystallographic symmetry, to direct methods an to phase extension. The first target will be the most frequent, and often the most challenging, cases in macromolecular crystallography: those of the molecules in the crystal lattice having and additional, non-crystallographic symmetry. The proposal is to develop the initial implementation of: - Identification of the rotational component of non-crystallographic symmetry by improving the self-rotation function; - A novel method to identify the molecule's shape and position ab initio; - Efficient use of the a priori information about the electron density inside the mask; - Ab initio phasing up to the intermediate resolution by conjugated gradient method; - Phase extension by state-of-the art solvent-flattening and NCS-averaging methods. These methods will be validated with a representative range of samples. It is expected that the developed framework will form a basis for the generally valid subsequent application that will led the structural biologists skip laborious and uncertain stage of developing heavy atom derivatized crystals. In terms of understanding the molecular biology, the highest expected impact is in structure determination of complex molecular assemblies.

描述（由申请人提供）：这笔赠款是为了解决阶段问题，这是结构生物学中经典的高风险/高影响力挑战。大分子结构的确定将通过识别非结晶对称性的新方法来改善，以指导方法A相扩展。第一个目标将是大分子晶体学中最常见的，通常是最具挑战性的情况：晶体晶格中具有和其他非晶体术对称性的分子的靶标。该建议是开发以下初始实施： - 通过改善自我移动函数来识别非结晶对称性的旋转成分； - 一种识别分子的形状和位置的新方法； - 有效地使用有关掩模内部电子密度的先验信息； - 从头开始​​，通过共轭梯度方法逐步逐步分辨为中间分辨率； - 通过最先进的溶剂纹理和NCS平均方法扩展阶段。这些方法将通过代表性范围的样本验证。预计开发的框架将为一般有效的后续应用构成基础，该框架将导致结构生物学家跳过艰辛的繁重阶段，发展为重度原子衍生化的晶体。在理解分子生物学方面，预期的最高影响是在复杂分子组件的结构上确定。