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

项目摘要/摘要 Phaser和Phenix中基于似然的结构解 通过提供生物分子的三维图像，大分子结晶学为更深入地理解维持生命的过程奠定了基础。因此，它在生物化学和分子生物学的基础科学以及制药业开发新疗法方面发挥着关键作用。基于最大似然统计概念的新算法将在Phenix软件包中包含的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，其他结晶学家应该会从他们的研究投资中获得更好的回报，结晶学方法应该变得更容易为专业知识较少的研究人员所使用。 大多数晶体结构现在都是通过分子置换技术来解决的，这种技术利用了相关分子的已知结构。通过将Phaser中基于似然的分子替换的敏感性与David Baker团队开发的程序Rosetta中的复杂建模技术相结合，分子替换的范围将进一步扩展到使用比目前可行的更远的相关起始模型。 第二种最流行的解决结构的方法是单波长反常衍射(SAD)位相，它与分子置换一样，只需要一个好的晶体的数据。一旦知道异常散射体的位置，相移的可能性强度将扩展到确定初始子结构的改进方法。 Phenix封装中自动化程度的提高将使新手结晶学家可以使用先进的算法，并将允许专业结晶学家探索结构解决方案的更多可能性。将开发利用一种晶型的部分溶液的方法，无论是通过分子置换还是实验相变，以解决其他晶型。将开发先进的方法来提炼结构对，以更清楚地了解它们之间的差异。

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.