? The aim of this proposal is to modernize the Rosetta software package for protein structure modeling in order to facilitate its continued development in parallel in multiple research groups and to promote the widespread use of the software in the scientific community. Achieving this aim would have a very positive impact on computational structural biology quite broadly because in many critical areas, the Rosetta methodology appears to be at least as good, if not better, than other approaches. By facilitating further development and application of the software by a large group of researchers throughout the scientific community, the power and usefulness of the software should increase enormously. Rosetta currently contains modules for de novo protein structure prediction, protein design, protein-protein docking, proteinprotein and proteim DNA interface design, protein-protein and protein-DNA interaction specificity prediction, loop modeling, and high-resolution protein structure refinement. These diverse applications provide stringent tests for the underlying potential functions and optimization methods that are shared by all modules, stimulating continued improvements in both areas. When such improved core elements are incorporated into the integrated Rosetta structure-modeling platform, all the individual applications reap the benefits. Integration of the different modules in a single package has made substantial advances possible by allowing multiple modules to be combined to address complex modeling problem. For example, the combined use of the structure prediction, protein design, and model refinement modules allowed the design of a novel protein fold with atomic level accuracy. To facilitate further integration of the different modules to attack problems such as flexible backbone protein-protein docking, and to facilitate the continued development of new features and functionality, the Rosetta package will be ported to C++ and modernized to an object-oriented design. To promote widespread use of the software, a comprehensive Rosetta web server will be developed, the modernized source code will be made freely available to the scientific community with extensive documentation, and researchers throughout the community will be encouraged to join the growing Rosetta development team. ? ? ?
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