De novo protein design: Crystallographic characterization of a synthetic peptide containing independent helical and hairpin domains

The Meccano (or Lego) set approach to synthetic protein design envisages co valent assembly of prefabricated units of peptide secondary structure. Ster eochemical control over peptide folding is achieved by incorporation of con formationally constrained residues like alpha-aminoisobutyric: acid (Aib) o r DPro that nucleate helical and beta-hairpin structures, respectively. The generation of a synthetic: sequence containing both a helix and a hairpin is achieved in the peptide BH17, Boc-Val-Ara-Leu-Aib-Val-Ala-Leu-Gly-Gly-Ph e-Val-DPro-Gly-Leu-Phe-Val-OMe (where Boc is t-butoxycarbonyl), as demonstr ated by a crystal structure determination. The achiral -Gly-Gly- linker per mits helix termination as a Schellman motif and extension to the strand seg ment of the hairpin. Structure parameters for C89H143N17O20. 2H(2)O are spa ce group P2(1), a 14.935(7) Angstrom, b=18.949(6)Angstrom, c=19.231(8)Angst rom, beta=101.79(4)degrees, Z= 2, agreement factor R-1 = 8.50% for 4,862 ob served reflections > 4 sigma(F), and resolution of;approximate to 0.98 Angs trom.