Proteins, one of the basic categories of biological molecules, are able to perform a wide variety of functions. Their functionality is due to their unique three-dimensional structures. There are tens of thousands of different proteins in living cells, yet in almost every case their individual structure can be described as belonging to just a handful of basic categories of shapes or "superfolds". Furthermore, the majority of the basic protein superfolds are symmetric in their general design. While this symmetric organization provides clues as to how these superfolds may have evolved (and also provides clues as to how novel proteins could be designed) the symmetry is "imperfect". The nature of this imperfection may reflect essential features associated with the ability of a protein to fold, and remain folded, into the unique structures required for their function. The project will study how protein structure, stability and folding are affected by the amino acid sequence symmetry within characteristically important central core region and turn regions of a representative member of the beta-trefoil symmetric superfold. The research will provide a major advance in our understanding of the relationship between the evolutionary mechanism of gene duplication and fusion and the requirements for a foldable polypeptide. Furthermore, the research will help further our understanding of how proteins can be effectively designed, and have a major impact upon the application of proteins in novel uses.
Broader Impact: The research will provide comprehensive training for graduate and undergraduate students in contemporary biophysical and biochemical methodologies, and foster one-on-one mentoring between graduate and undergraduate students that is essential for effective training.
