The a-Oligopeptide Precedent: from Antibiotic Gramicidin A to Poly-Gin Aggregates in Huntington's Disease
Mixed helices, also termed b-helices by virtue of this similarity to b-sheet type structures, were proposed in the early 1970s independently by Ramachandran and Chandrasekharan , and Urry  for a-oligopeptides with a regularly alternating sequence of d and l residues (d,l-peptides) such as the linear penta-decapeptide antibiotic gramicidin A (HCO-Val-Gly-Ala-d-Leu-Ala-d-Val-Val-d-Val-Trp-d-Leu-Trp-d-Leu-Trp-d-Leu-Trp-NH-(CH2)-OH), i.e. by repeating a pair of (f, c) angles with values lying in the allowed b-sheet region of the Ramachandran map for l and d residues, respectively. The H bonds are formed alternatively in forward and backward directions along the sequences thus closing intertwined pseudo rings of different sizes (Fig. 2.8). b-Helices formed by d,l-peptides are characterized by their structural polymorphism [131-135]. They can be either right- or left-handed depending on parameters such as sequence, length and environment. Various periodicity and hence pore size have been predicted and found experimentally. Finally, b-helices can exist either as single helices stabilized by parallel H bonds or as parallel (or antiparallel) double helices. Gramicidin A, for example, depending on its surrounding environment has been found to form either single stranded or double stranded b-helical conformations with residues per turn ranging from 5.6 to 7.2 [136-139].
Proteins also fold into right- and left-handed b-type helical structures with larger periodicities [140-142]. The first parallel b-helix fold (right-handed) was discovered by Yoder and co-workers in the structure of Pectate Lyase C . The repeating unit (i.e. b-helical turn) in such b-helices is formed by three strand segments connected by three loops and generally comprises 15-23 residues. A large "loopless" b-helical nanotube with 20 residues per helical turn has been proposed by Perutz and co-workers to account for the X-ray diffraction patterns of fibers of a poly-l-Gln peptide (exon-1 peptide of huntingtin) . In addition to being relevant to Huntington's disease, this model may also serve to interpret structures of amyloid fibrils associated with various neurodegenerative diseases. It is worth noting that this structure which features repetition of a pair of (f, c)
angles with nearly opposite values (f = 160°, ci = —170°; f2 = —161°, c2 = 178°); is remarkably close to a d,l-peptide b-helical fold.
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