Project 3: Likelihood-based structure solution in Phaser and Phenix

项目 3：Phaser 和 Phenix 中基于似然的结构解决方案

• 批准号: 8382317
• 负责人: Randy J Read
• 金额: $ 15.83万
• 依托单位: UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8382317
• 关键词: Accounting; Adopted; Algorithms; Automation; Basic Science; Binding; Biochemistry; Biological; Collaborations; Computers; Coupling; Crystallography; Data; Development; Drug Industry; Error Sources; Investments; Ions; Joints; Language; Life; Ligands; Likelihood Functions; Maps; Methods; Minority; Modeling; Molecular; Molecular Biology; Nucleic Acids; Occupations; Pathway interactions; Performance; Phase; Play; Positioning Attribute; Process; Proteins; Pythons; Research; Research Personnel; Rotation; Solutions; Specialist; Structure; Techniques; Time; Translations; Work; abstracting; base; density; electron density; improved; molecular scale; novel; programs; success; three dimensional structure; tool

Project Summary/Abstract Likelihood-based structure solution in Phaser and Phenix By providing three-dimensional pictures of biological molecules, macromolecular crystallography underpins a deeper understanding of the processes that maintain life. As such, it plays a key role in the basic science of biochemistry and molecular biology, as well as the development of new therapies by the pharmaceutical industry. New algorithms, based on the statistical concept of maximum likelihood, will be developed in the program Phaser an6 incorporated in the Phenix package to determine the 3D structures of proteins and nucleic acids more quickly and more automatically. With these new tools, other crystallographers should gain a better return on the investment made in their research, and crystallographic methods should become accessible to researchers with less specialist expertise. The majority of crystal structures are now solved by the technique of molecular replacement, which exploits the known structure of a related molecule. By coupling the sensitivity of likelihood-based molecular replacement in Phaser with sophisticated modeling techniques in the program Rosetta developed by the group of David Baker, the reach of molecular replacement will be further extended to use starting models that are more distantly related than currently feasible. The next most popular method of structure solution is single-wavelength anomalous diffraction (SAD) phasing, which shares with molecular replacement the advantage of requiring data from only one good crystal. The strength of likelihood for phasing, once the positions of the anomalous scatterers are known, will be extended to improving methods for determining the initial substructure. Increased automation in the Phenix package will make advanced algorithms available to novice crystallographers, and will allow expert crystallographers to explore many more possibilities for structure solution. Methods will be developed to exploit a partial solution in one crystal form, either by molecular replacement or experimental phasing, to solve additional crystal forms. Advanced methods will be developed for refining pairs of structures, to give a clearer picture of the differences between them.

项目总结/摘要 Phaser和Phenix中基于可能性的结构解决方案 通过提供生物分子的三维图像，大分子晶体学支持对维持生命的过程的更深入理解。因此，它在生物化学和分子生物学基础科学以及制药行业开发新疗法方面发挥着关键作用。新的算法，基于最大似然的统计概念，将在Phaser an 6程序中开发，该程序被纳入Phenix软件包，以更快、更自动地确定蛋白质和核酸的3D结构。有了这些新工具，其他晶体学家应该从他们的研究投资中获得更好的回报，晶体学方法应该可以让专业知识较少的研究人员使用。 现在大多数晶体结构都是通过分子置换技术解决的，该技术利用了相关分子的已知结构。通过将Phaser中基于可能性的分子置换的灵敏度与大卫贝克小组开发的罗塞塔程序中的复杂建模技术相结合，分子置换的范围将进一步扩展到使用比目前可行的更远相关的起始模型。 下一个最流行的结构解决方法是单波长异常衍射（SAD）定相，它与分子置换共享只需要一个好晶体的数据的优势。一旦已知异常散射体的位置，定相的可能性强度将被扩展到改进用于确定初始子结构的方法。 Phenix软件包中自动化程度的提高将使晶体学新手能够使用先进的算法，并使晶体学专家能够探索更多的结构解决方案。将开发方法来利用一种晶体形式的部分溶液，通过分子置换或实验定相，以解决其他晶体形式。将开发先进的方法来细化成对的结构，以更清楚地了解它们之间的差异。