Conformational analysis of cyclic analogues of the Saccharomyces cerevisiae alpha-factor pheromone

Analogues of the alpha-factor mating pheromone (WHWLQLKPGQPMY) from Saccharomyces cerevisiae in which the side chains of residues 7 and 10 were joined by lactam bonds were studied by nmr and molecular modeling. These investigations were carried out to discern the effect of lactam ring size on conformation and to ascertain whether the side chain i to i + 3 cyclized tetramers [H. R. Marepalli et al. (1996) Journal of the American Chemical Society, Vol. 118, pp. 6531-6539] can be considered as conformation-constraining building blocks when introduced into a long peptide chain. Nuclear Overhauser effect constraints, temperature coefficients, and backbone torsional angles were derived from 1H-nmr spectra measured in DMSO-d6. Modeling studies using the above constraints indicate that the lactam regions of the tridecapeptides assume various combinations of type II beta-turns, gamma-turns, and gamma 1-turns, but never type I beta-turns. These investigations provide evidence that the tetrapeptide building blocks retain their preferred conformations in larger molecules and can be used to control the architecture of regions of such peptides.