CHIMERA EXTENSIONS FOR IMP

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 与加州大学旧金山分校的Andrej Sali教授的团队合作，我们将实现Chimera扩展和Web服务，以支持蛋白质和蛋白质复合物在三个主要领域的建模： 1)单个蛋白质的比较建模和环建模。 具体来说，我们将把实现的算法作为广泛使用的 比较建模程序Modeller，并将它们作为Web服务提供。然后，我们将增强Chimera，以便用户提供要建模的序列和用作模板的结构，可以使用此Web服务来生成模型。 2)使用cryoEM和蛋白质组学数据确定大型组件的结构。 我们将使用Chimera来查看和指导使用cryoEM和蛋白质组学数据确定IMP大型组件结构的过程。用户将能够在优化过程的中间步骤查看和细化模型。嵌合体将被用于显示密度图和一个锚图，该图显示了组装体中蛋白质质心的大致位置以及它们之间的相互作用。锚图形由MultiFit计算。我们将支持以下与MultiFit过程交互的方式：1）在锚图指导下的密度中手动定位和定向蛋白质，然后调用MultiFit进行局部细化; 2）在锚点上手动定位蛋白质，但使用MultiFit搜索所有可能的方向; 3）在MultiFit的个体约束值和总体评分的动态反馈指导下，在组装模型内手动定位和定向蛋白质;以及4）在没有任何初始定位的情况下运行MultiFit，但是允许在如上所述的中间步骤处进行手动细化。 3)使用小角X射线散射（SAXS）数据进行结构细化和拟合。 我们将支持使用实验和计算的SAXS配置文件，以指导修改和改进模型结构。将实现以下结合3D结构和SAXS轮廓的方法：1）同时加载结构和SAXS轮廓并一起显示它们; 2）计算并显示部分或全部显示结构的SAXS轮廓; 3）将计算的SAXS轮廓拟合到实验的SAXS轮廓并一起显示它们; 4）重新计算SAXS轮廓 当结构被交互地修改（例如，通过改变扭转角或相对于彼此移动蛋白质）时自动地进行;以及5）改进组装模型以更好地拟合实验SAXS谱 使用IMP Web服务。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. In conjunction with Prof. Andrej Sali's group at UCSF, we will implement Chimera extensions and web services to support protein and protein complex modeling in three main areas: 1) Comparative modeling and loop modeling of individual proteins. Specifically, we will take the algorithms implemented as part of the widely used comparative modeling program Modeller, and make them available as a web service. We will then enhance Chimera so that a user providing a sequence to be modeled and a structure to be used as the template could use this web service to produce a model. 2) Determination of the structures of large assemblies using cryoEM and proteomics data. We will use Chimera to view and guide the process of determining the structures of large assemblies with IMP using cryoEM and proteomics data. The user will be able to view and refine models at intermediate steps of the optimization process. Chimera will be used to display the density map and an anchor graph, which shows the approximate positions of protein centroids in the assembly and the interactions among them. The anchor graph is calculated by the MultiFit. We will support the following ways of interacting with the MultiFit process: 1) manual positioning and orientating of the proteins in the density guided by the anchor graph and then calling MultiFit for local refinement; 2) manual positioning of proteins on anchor points but using MultiFit to search all possible orientations; 3) manual positioning and orientating of proteins within the assembly model guided by dynamic feedback of the individual restraint values and overall score from MultiFit; and 4) running MultiFit without any initial positioning but allowing manual refinement at intermediate steps as described above. 3) Structural refinement and fitting using Small Angle X-Ray Scattering (SAXS) data. We will support the use of experimental and computed SAXS profiles to guide the modification and refinement of modeled structures. The following ways of combining 3D structure and SAXS profiles will be implemented: 1) loading a structure and SAXS profile simultaneously and displaying them together; 2) computing and displaying the SAXS profile for part or all of the displayed structure; 3) fitting the computational SAXS profile to the experimental one and displaying them together; 4) recalculating the SAXS profile automatically as the structure is interactively modified (for example, by changing torsion angles or moving proteins relative to each other); and 5) refining the assembly model to better fit the experimental SAXS profile using an IMP web service.