Molecular carpentry: Piecing together helices and hairpins in designed peptides

The design of a peptide that contains two distinct elements of secondary st ructure, helix and beta -hairpin, is described. Two designed 17-residue pep tides: Boc-Val-Ala-Leu-Aib-Val-Ala-Leu-Gly-Gly-Leu-Phe-Val-D-Pro-Gly- Leu-P he-Val-OMe (I) and Boc-Leu-Aib-Val-Ala-Leu-Aib-Val-Gly-Gly- Leu-Val-Val-D-P ro-Gly-Leu-Val-Val-OMe (II) have been conformationally characterized by NMR spectroscopy. Peptides I and II contain a seven-residue helical module at the N terminus and a eight-residue beta -hairpin module at the C terminus, which are connected by a conformationally flexible Gly-Gly segment. The cho ice of the secondary-structure modules is based upon prior crystallographic and spectroscopic analysis of the individual modules. Analysis of 500 MHz H-1 NMR data, recorded as solutions in methanol, suggests that the observed pattern of chemical shifts (3)J(HN-C alphaH) values, temperature coefficie nts of the NH chemical shifts, and backbone inter-residue nuclear Overhause r effects favor helical structures for residues 1-7 and beta -hairpin struc tures for residues 10-17 The spectroscopic data are compatible with termina tion of the helical segment by formation of a Schellman motif, this restric ts Gly(8) to a left-handed alpha -helical conformation. Gly(9) is the only residue with multiple conformational possibilities in phi,psi space. Possib le orientations of the two secondary-structure modules are considered. This study validates the use of stereochemically rigid peptide modules as prefa bricated elements in the construction of synthetic protein mimics.