CHIMERA EXTENSIONS FOR IMP

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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.