Project 2 Exploiting new sources of information in density-modification

项目摘要/摘要 在密度修正和模型推算中开拓新的信息源 这是一个项目，旨在开发算法，以低于3-3.5A的分辨率构建代表大分子晶体结构的原子模型，结合密度修正和精细化的能力，并使用Phenix环境中所有强大的工具来自动化结构确定过程。 该项目的成功将使结构确定更加稳健和快速，导致更准确的模型，并允许使用较低分辨率的数据进行结构确定。该项目将与伯克利大学、杜克大学和剑桥大学的小组密切合作进行。所开发的方法的增强的能力将允许以比目前可行的更低的分辨率进行结构测定的自动化，为世界各地的学术界、政府和工业界的结构生物学家节省大量的时间和金钱，并允许进行当手动进行结构测定时完全不切实际的错误分析和验证水平。 在Phenix项目的过去5年中，我们与伯克利大学、杜克大学和剑桥大学的团队合作，开发了使用MAD、SAD和MIR方法的任意组合的全自动结构确定X射线结晶学程序。作为这些高水平程序的基础，我们开发了新的方法来评估实验电子密度图的质量，从密度图中识别非晶体对称性，多晶体平均，以及未知的识别 配体，以及一套用于快速建模的新工具。此外，我们已经开始与剑桥集团和贝克实验室进行令人兴奋的合作，将结构建模领域的算法与结晶学领域的互补算法相结合。 我们现在计划将我们的努力集中在开发方法上，这些方法将加快确定今天仍然具有挑战性的结构。这些具有挑战性的结构包括那些数据仅扩展到3.0-3.5A或更差分辨率的结构，那些具有弱实验相信息的结构，以及那些具有来自遥远同源模型的分子替换信息的结构。为了实现这一目标，我们建议与伯克利、剑桥和杜克大学合作开发依赖分辨率的建模工具，将基于晶体图案的建模与结构建模领域的基于能量的互补建模工具相结合，并开发一个框架，将密度修改和精化合并到一个更强大的过程中。在这些新努力的同时，我们将继续发挥我们在开发集成的、灵活的和易于使用的用于大分子结构测定的菲尼克斯系统方面的作用。 这项工作将使结构生物学家能够确定大分子的三维结构，这对了解疾病和维护人类健康至关重要。

Project Summary/Abstract Exploiting new sources of information in density-modification and model-bullding This is a project to develop algorithms for constructing atomic models representing macromolecular crystal structures at resolutions worse than 3 - 3.5 A, for combining the power of density modification and refinement, and for using all the powerful tools in the Phenix environment to automate the structure determination process. Success in this project will make structure determination more robust and more rapid, lead to more accurate models, and allow structure determination to be carried out with lower-resolution data. The project will be carried out in close collaboration with the Berkeley, Duke and Cambridge groups. The increased power of the methods developed will allow automation of structure determination at lower resolutions than is currently feasible, saving large amounts of time and money for structural biologists around the world in academia, government and industry, and allowing levels of error analysis and validation that are completely impractical when structure determination is done manually. During the past 5 years of the Phenix project we have worked with the Berkeley, Duke and Cambridge groups to develop fully automated procedures for structure determination X-ray crystallography with any combination of MAD, SAD, and MIR methods. As a foundation for these high-level procedures, we have developed new methods for evaluation of the quality of experimental electron density maps, for identification of noncrystallographic symmetry from density maps, for multi-crystal averaging, and for identification of unknown ligands, and a suite of new tools for rapid model-building. Further we have embarked on an exciting collaboration with Cambridge group and the Baker laboratory to combine algorithms from the structure modeling field with complementary algorithms from the crystallography field. We plan now to focus our efforts on developing methods that will accelerate the determination of structures that remain challenging today. These challenging structures include those with data extending only to resolutions of 3.0 - 3.5 A or worse, those with weak experimental phase information, and those with molecular replacement information from distant homology models. To achieve this goal, we propose to work with the Berkeley, Cambridge and Duke groups to develop resolution-dependent model-building tools, to combine crystallographic pattern-based model-building with complementary energy-based modeling tools from the structure-modeling field, and to develop a framework that will merge density modification and refinement into a single more powerful procedure. In parallel with these new efforts we will continue our role in the development of an integrated, flexible, and easy-to-use Phenix system for macromolecular structure determination. This work will allow structural biologists to determine 3-dimensional structures of macromolecules that are of key importance in understanding disease and maintaining human health.