Il. Karle et al., DESIGN OF 2-HELIX MOTIFS IN PEPTIDES - CRYSTAL-STRUCTURE OF A SYSTEM OF LINKED HELICES OF OPPOSITE CHIRALITY AND A MODEL HELIX-LINKER PEPTIDE, Folding & design, 2(4), 1997, pp. 203-210
Background: An attempt is being made to produce two-helix bundles that
are soluble in apolar media, without the use of a rigid template. The
approach relies on the use of stereochemically constrained amino acid
s for helix construction, while a flexible linker is obtained by the u
se of an is an element of-aminocaproic acid residue (Acp). The Acp lin
ker has appropriate NH and COOH termini to connect to the N and C term
ini of the helices, a flexible (CH2)(5) moiety and sufficient length t
o make the desired assembly. Results: The conformations in crystals (d
etermined by X-ray diffraction analyses) are described for a partial a
ssembly consisting of a 7-residue helix with Acp (helix-Acp) and for t
wo assemblies of 7-residue helices with Acp (helix-Acp-helix) in which
the chiralities of the helices are L,L (already published) and L,D (t
his publication). The Acp linker is extended away from the helix in th
e L,L analog in a zig-zag manner, but assumes a helical conformation i
n the L,D analog. The two helices in the L,L and L,D analogs are displ
aced laterally by the linker, but in neither case has the linker folde
d the molecule into the desired U-conformation. Cell parameters for eu
-Acp-D-Val-D-Ala-D-Leu-Aib-D-Val-D-Ala-D-Leu-OMe are space group P4(1)
with a = b = 10.094(6) Angstrom and c = 93.383(1 2) Angstrom. Conclus
ions: Strong hydrogen bonds (NH ... O=C) between the displaced helices
of one molecule and the displaced helices of a neighboring molecule,
which form near the linker of each helix-linker-helix assembly, appear
to dominate in both the L,L and L,D crystal. The (CH2)(5) segment of
the linker readily adopts different conformations that result in the L
and D helices packing in a similar spatial motif. Greater conformatio
nal control at the linking segment or introduction of specific interhe
lix interactions may be necessary in order to achieve U-type folding b
etween neighboring helices in a single molecule.