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.
Ludwig Institute for Cancer Research, Tumor Biology Branch, Melbourne, Australia.
Gideon
G
Kowadlo
Nathan E
NE
Hall
Antony W
AW
Burgess
D000818:Animals; D003198:Computer Simulation; D006801:Humans; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry*; D017510:Protein Folding; D017433:Protein Structure, Secondary
D010455:Peptides