The availability of accurate three-dimensional structtires for important biomolecules such as proteins and nucleic acids can greatly aid in the understanding of their fimction, as well as in the rational design of pharmaceutical compounds. However, the structural database is relatively smaii. Structures are often built using comparative modeling. but these are typically less accurate in loop regions. A new approach to predict highly accurate loop conformations in proteins will be developed, with specific application to antibody CDR loops. This mean-field method will dramatically increase sampling of alternate conformations while maintaining compatibility with state of the art simulation techniques such as molecular dynamics in explicit solvation. Individual water molecules often have structural roles, and replacement with a continuum model may result in an unacceptable loss of accuracy. This is a key advantage of the method over those currently in use. Since the method is enezgy-based it is more general than those using databases, and will improve many areas of structural modeling. The project will consist of development of an enhanced locally Enhanced Sampling approach. This will be applied to successively more difficult problems in prediction of antibody loops. Initial studies will focus on reproducing known cases of induced fit for the important H3 loop, followed by true prediction for systems in which the H3 conformation is unknown. These will provide new insights into the determinants of induced fit, the role of solvent and key structural details for several antibodies of biomedical importance. Subsequent studies will predict all 6 loops in antibody CDR regions for several catalytic antibodies. These structures will aid in understanding the factors that influence the catalytic activity of these antibodies, and how efficiency is aifected by loop flexibility, solvent molecules or deficiencies in transition state analogs against which the antibodies are raised. The method will be extended to the prediction not only of antibody conformations, but also the structures of antibody-antigen complexes. This information can be critical to the understanding of these important biomolecular interactions.
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