| If the rules that govern complex atomic interactions are completely understood, then the greatest test would be to apply them to a new paradigm. The application of existing computational protein design methods and parameters to the beta-peptide scaffold serves as this test. The paucity of structural data and lack of diverse examples employing this scaffold pose a great intellectual deficit in the ability to predict secondary structure and peptide-peptide interactions. I present tools, techniques and examples of successful rational beta-peptide design. Through detailed modeling, rotameric preferences for this clans of compounds have been determined which were later validated experimentally. Using this infrastructure, secondary structure modeling has also been successfully achieved for this scaffold through the de novo design of a self-associating beta-peptide oligomer. Finally, as a bridge to practical applications, the first transmembrane beta-peptide was designed and characterized which also specifically binds its intended biological target integrin alphaIIB. Together, these efforts provide credibility to our ability to successfully apply highly parameterized design techniques to new scaffolds. |
