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: 8227534
• 负责人: Randy J Read
• 金额: $ 15.91万
• 依托单位: UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8227534
• 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.

项目概要/摘要 Phaser 和 Phenix 中基于似然的结构解决方案 通过提供生物分子的三维图像，大分子晶体学有助于更深入地了解维持生命的过程。因此，它在生物化学和分子生物学的基础科学以及制药行业新疗法的开发中发挥着关键作用。基于最大似然统计概念的新算法将在 Phenix 软件包中的 Phaser an6 程序中开发，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，其他晶体学家应该能从他们的研究投资中获得更好的回报，并且专业知识较少的研究人员也可以使用晶体学方法。 现在，大多数晶体结构都是通过分子置换技术来解决的，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替换的敏感性与 David Baker 小组开发的 Rosetta 程序中复杂的建模技术相结合，分子替换的范围将进一步扩展到使用比当前可行的关系更远的起始模型。 下一个最流行的结构解决方法是单波长反常衍射 (SAD) 定相，它与分子替换一样具有只需要来自一个良好晶体的数据的优点。一旦已知异常散射体的位置，定相可能性的强度将扩展到改进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新手晶体学家能够使用先进的算法，并使专家晶体学家能够探索结构解决方案的更多可能性。将开发方法来利用一种晶型的部分解决方案，通过分子置换或实验定相来解决其​​他晶型。将开发先进的方法来精炼结构对，以更清楚地了解它们之间的差异。