De novo design of β-helical polypeptides

Abstract

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

• Protein design
• protein folding
• molecular dynamics
• nanostructures
• drug carriers

Notes

^† A notable exception is Mfpa, a recently described quadrilateral pentapeptide repeat β-helix (Vetting et al. 2006).