Stereochemical constraints in peptide design: Analysis of the influence of a disulfide bridge and an α‐aminoisobutyryl residue on the conformation of a hexapeptide

The competing effects of a disulfide bridge and an alpha-aminoisobutyryl residue (Aib) in determining the conformation of a hexapeptide have been investigated, by comparing the cyclic disulfide [sequence: see text] and the acylic peptide Boc-Cys (SBzl)-Val-Aib-Ala-Leu-Cys (SBzl)-NHMe (2). Previously published nmr and crystallographic studies [R. Kishore, S. Raghothama, and P. Balaram (1987) Biopolymers, Vol. 26, pp. 873-891; I. L. Karle, R. Kishore, S. Raghothama, & P. Balaram, (1988) Journal of the American Chemical Society Vol. 110, pp. 1958-1963] have established an antiparallel beta-hairpin structure for 1 with a central Aib-Ala beta-turn. A comparison of nmr data for 1 and 2 in chloroform and dimethylsulfoxide reveals that the acyclic peptide is conformationally labile. Evidence for a 3(10)-helical conformation in CDCl3 is obtained from sensitivity of NH chemical shifts to temperature and solvent perturbation and low JHNC alpha H values. Studies in solvent mixtures establish a conformational transition on going from CDCl3 to (CD3)2SO. The changes in NH nmr parameters, together with the observation of several interresidue C alpha i H-Ni+1H nuclear Overhauser effects support a conformation having a central beta-turn with extended arms in (CD3)2SO. A single Aib residue appears to stabilize a helix in apolar solvents, for the acyclic hexapeptide, while the disulfide bridge serves to lock the beta-hairpin conformation.