Crystal structure of a hydrophobic 19-residue peptide helix containing three centrally located D amino acids.

Abstract

The design of the synthetic 19-residue peptide Boc-Leu-Aib-Val-Ala-Leu5-Aib-Val-D-Ala-d-Leu-Leu10-Val-Phe-Val-Aib-D-Val15-Leu-Phe-Val-Val-OMe (Aib, alpha-aminoisobutyric acid; OMe, methyl ester) was intended to produce a crystalline peptide with independent helical and hairpin domains. The design was partially based on an octapeptide with the same sequence as residues 11-18 above, which was shown to fold into a beta-hairpin in the crystal. However, the crystal structure of the present peptide provided a surprising result. The conformation is the longest characterized right-handed alpha-helix, with as many as three internal d residues in the sequence. The completely helical structure was also unexpected, because beta-branched residues such as Val have a low propensity for helix formation in proteins. The helical peptides in the present structure assemble to form hydrophobic channels that accommodate five toluene molecules per peptide along the length of the channel. The structural results illustrate the similarity in energetics between helical and beta-hairpin conformations for peptides containing Aib residues. The crystallographic parameters for C107H179N19O22.3H2O.2.5 toluenes are: space group C2, a = 34.679(3) A, b = 12.866(1) A, c = 31.915(3) A, beta = 96.511(8) degrees, V = 14,148 A3, Z = 4, dcalc = 1.099 g/cm3, and agreement factor R1 = 10.2%.