Our long-term objective is to develop biotechnology software, based on the FIRST algorithm (Floppy Inclusions and Rigid Substructure Topography) that will offer researchers at pharmaceutical and biotechnology companies a useful set of tools for evaluating protein domains and conformational flexibility for drug design and protein engineering. Developed by an interdisciplinary team, FIRST applies concepts from graph theory to protein structural analysis. The goal of Phase I is to develop and validate FIRST for several proteins with well-characterized conformational states by optimizing the modeling of hydrogen bonds. The rigid and flexible regions identified by FIRST will be compared with traditional measures of flexibility including crystallographic temperature factors and molecular dynamics trajectories. The FIRST algorithm can be used in real time; for example, it can analyze a 200 residue protein and identify flexible hinges and rigid substructures within a fraction of a second using a Pentium PC. The initial product will provide a detailed map for locating rigid motifs and flexible linkages within proteins. This will give the pharmaceutical biochemist the ability to explore, in real time, the effects on ligand structural stability and docking that result from making specific modifications to a protein. PROPOSED COMMERCIAL APPLICATIONS: The commercial applications are to market scientific software for the real-time characterizing of rigid and flexible regions in proteins for crystallographers and pharmaceutical biochemist, as well as an interactive design tool for molecular biologists for evaluating and conformational effects of site-directed mutations
