De novo design of beta-helical polypeptides

Many proteins, including several growth factor receptors such as the IGF-1R and EGFR family, contain variants of the beta-helix fold. Inspection of the irregular protein beta-helices suggested that different families of regular beta-helical polypeptides can be designed using a series of hinged vectors and the constraints imposed by the geometry of a peptide backbone. We have conceived beta-helices with five and six beta-strands per turn and designed, in detail, a series of regular beta-helices with rhomboidal or triangular cross-sections. Each beta-helix was modeled by threading C(alpha) atoms to follow the vectorial beta-helix and then creating the H-bonded polypeptide backbone and appropriate side-chain orientations. The conformational stability of these regular beta-helices was assessed using molecular dynamics simulations. Several potential repeat amino acid sequences were identified for different geometries of beta-helix. Regular beta-helices offer new possibilities for the study of protein folding, the production of nanofibers, catalysts, inhibitors of growth factor receptors and drug carriers.