Peptide design. Structural evaluation of potential nonhelical segments attached to helical modules

Abstract

The conformations of three decapeptides containing a helical heptapeptide module attached to a potentially helix destabilizing tripeptide segment have been investigated in single crystals. X-ray diffraction studies of the sequence Boc-Gly-Dpg-X_xx-Val-Ala-Leu-Ab-Val-Ala-Leu-OMe (X_xx = Leu (l), Pro (2), and Ala (3); Dpg = alpha,alpha-di-n-propylglycine; Aib = alpha-aminoisobutyric acid) reveal helical conformations for the segment 2-9 in all three peptides. In 1 and 2 Gly(1) is not accommodated in the right-handed helix and adopts a left-handed helical conformation with positive phi, psi values. The terminal blocking group extends away from the helix in 1 and 2. In 3 the helix is continuous, encompassing residues 1-9. The Dpg residues in all three cases adopt helical conformations, even when flanked by two helix destabilizing residues as in 2. These findings suggest that the higher alpha,alpha-dialkyl residues are good helix promoters although theoretical calculations suggest the existence of a pronounced energy minimum in fully extended regions of conformational space. None of the peptides pack efficiently. The register between helices in the head-to-tail region is not good, with disordered water molecules serving as hydrogen bond bridges and as space fillers. The crystallographic parameters follow. 1: Xxx = Leu, C54H98N10O13.2H2O.C3H7OH, P212121, a = 16.399(3) Å, b = 18.634(3) Å, c = 23.241(4) Å. 2: Xxx = Pro, C53H94N10O13.2H2O, P212121, a = 16.468(4) Å, b = 18.071(4) Å, c = 23.397(5) Å. 3: Xxx = Ala, C51H92N10O13^∗ xH2O, P21212, a = 19.289(7) Å, b = 35.950(12) Å, c = 9.570(3) Å.