Unified automated model building & refinement for biological crystallography

描述(申请人提供)：一般的结构生物学，特别是蛋白质结构倡议，旨在了解大分子、它们的络合物和家族的结构和功能，创造一种知识，为丰富的生物医学应用进一步探索。X射线结晶学通过提供感兴趣的生物分子的详细原子模型，已经成为帮助研究生物现象的最常用的方法。为了最大限度地提高X射线结晶学的效率，蛋白质结构测定中劳动密集型、重复性任务的自动化至关重要。因此，在电子密度图中建立原子模型的步骤必须快速、可靠和高度自动化。ARP/WARP软件开创了这一自动化步骤，并帮助获得了大量新的大分子结构。ARP/WARP的科学发展，主要由美国国立卫生研究院在过去三年中资助，标志着整个软件包的相当大的进步。开发的算法和科学概念允许构建更完整的模型，并扩展对较低分辨率电子密度图的解释。通过图形用户界面和基于WWW的远程提交任务的执行，非专家研究人员可以更容易地使用该软件。ARP/WARP软件在速度和收敛方面的整体性能得到了改善。在申请续期的过程中，我们将扩展该项目的目标，以实现大分子三维结构测定的无缝自动化，同时我们将提供更完整和更有效的模型，并降低实验衍射数据的分辨率。我们将通过以下方式实现我们的目标：进一步开发基于模式识别的算法；改善结构确定不同步骤之间的联系，重点是大的和多聚体结构；提供真正完整的模型，包括有序的表面区域，特别强调建立结合配体；开发能够根据积累的历史做出基本决策的‘专家控制系统’；以及继续改善社区对软件的可访问性。

DESCRIPTION (provided by applicant): Structural Biology in general and the Protein Structure Initiative in particular, aim to understand the structure and function of macromolecules, their complexes and families, creating a knowledge that is further explored for a wealth of biomedical applications. X-ray crystallography has become the most commonly used method to assist the investigation into biological phenomena by providing detailed atomic models of the bio- molecules of interest. To maximize the efficiency of X-ray crystallography, automation of labor intensive, repetitive tasks in protein structure determination is crucial. As such, the step of building an atomic model in the electron density map has to be made fast, reliable and highly automated. The ARP/wARP software has pioneered this automation step and helped to obtain a large number of novel structures of macromolecules. Scientific developments in ARP/wARP, mostly funded by the NIH over the last three years, landmarked considerable advancement of the overall software package. The developed algorithms and scientific concepts allow construction of more complete models and to extend the interpretation of lower resolution electron density maps. The software became easier to use for non-expert researchers via graphical user interfaces and WWW-based execution of remotely submitted tasks. The overall performance of the ARP/wARP software in terms of speed and convergence was improved. In the course of the requested renewal of the grant we will extend the aims of the project towards seamless automation of macromolecular 3-D structure determination, while we will deliver more complete and validated models with lower resolution of the experimental diffraction data. We will achieve our goals by developing further the pattern recognition-based algorithms; improving interlinks between different steps of structure determination with emphasis to large and multimeric structures; delivering truly complete models including poorly ordered surface regions, with special emphasis to building bound ligands; developing an 'expert control system' that would be capable of basic decision making based on the accumulated history; and by continuing to improve the accessibility of the software by the community.