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a-Peptides Novel Secondary Structures Take Shape.

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B-Peptides: Novel Secondary Structures Take Shape
Ulrich Koert*
The prerequisite for the biological function of any protein is
the folding of the peptide strand composed of a-amino acid
residues into the corresponding active conformation. Important
intermediates during the folding process are domains having a
particular secondary structure. Secondary structures of a-peptides have been studied intensively; the most common structural
themes are the a-helix and the a-sheet. Is the occurrence of
secondary structures limited to a-peptides only?
Recent results from the groups led by D. Seebach“-31 and S.
Gellman[4s’I show that ,8-peptides[61such as 1 and 2 also may
Figure 1. 3,-Helices of the B-peptides 1 and 2, respective slde views (A and C) and
views along the helix axis (B and D). The intramolecular hydrogen bonds are drawn
in violet. For clarity, only one carbon atom in each side chain in A and B is shown
form well-defined, remarkably stable secondary structures. The
required a-amino acid building blocks are accessible, for example, by Arndt - Eistert homologation of the corresponding
a-amino acids.“]
Seebach et al. examined a-peptides of type l.[’- 3 J NMR studies in solution (MeOH, pyridine) prove the presence of a helical
secondary structure (Figure 1A, B). An oligomer containing
only six P-amino acid residues forms a stable helix! With a-peptides, a stable secondary structure usually occurs first for the
15-20-mers. Exceptions are shorter homo-a-peptides and apeptides containing proline or 2-amino-2-methylpropanoic acid
[*] Prof. Dr. U. Koert
Institut fur Chemie der Humboldt-Universitat
Hessische Strasse 1-2, D-10115 Berlin (Germany)
Fax: Int. code +(30)2093-2766
0 WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1997
(Aib). Gellman et al. proved the presence of an almost identical
secondary structural motif in type 2 P-peptides by X-ray structure analysis and conformational studies in solution (Figure 1 C, D) .[41 The new helical secondary structure is stabilized
by hydrogen bonds forming a 14-membered ring (the a-helix
contains 13-membered rings). Exactly three amino acid residues
are required to form one turn of the helix. Therefore the new
secondary structure is designated a 3 ,-helix. The known a-helix
with 3.6 a-amino acids per turn is a 3.6,-helix.
An a-peptide composed of naturally occurring L-a-amino
acids forms, with respect to its helical sense, a 3.6,-P-helix. In
contrast, a P-peptide like 1 made of homologated L-a-amino
acids forms a 3,-M-helix (Figure 2).
H~~ much stereochemical “information” in the P-PePtide is
necessary to establish the new secondary structure? Gellman
0570-0S33/97/3617-1836S 17.50+ .50/0
Angew. Chem. Int. Ed. Engl. 1997,36, No. 17
a-peptide, 3.6,-P-helix
/3-peptide, 31-M-helix
Figure 2. Schematic representation of the helix of a peptide composed of L-a-amino
acids (left) and one composed of L-8-amino acids (right). The arrows follow the
helix dipoles. The a-peptide is depicted as a 3.6,,- or a-helix (Pconfiguration with
3.6 a-amino acid residues per turn and a pitch of 5.4
/$peptides consisting of
homologated L-a-amino acids form a 3,,-helix (peptide nomenclature) or 3,-helix
(crystallographic notation) of M configuration ( 3 8-amino acid residues per turn
and a pitch of 5.0 A).
when heated to 350 K. Within only 200 ps the helical conformation is re-established!r71Without stereogenic centers in the
P-peptide backbone, the formation of a 3,-helix is not preferred.", 2]
The trans-substituted cyclohexane ring in Gellman's 1-amino
acids has a strong influence on the formation of the hydrogen
bonds making up the 14-membered ring in the 3,-helix. When
the corresponding trans-substituted cyclopentane p-amino acid
is employed, an altered helix with 12-membered-ring hydrogen
bonds results.[51
In addition to the linear 8-peptides, Seebach et al. synthesized
cyclic /I-peptides such as 3 and 4 and studied their conformations.['] In the solid state these cyclo-P-peptides form cylindrical
stacks stabilized by hydrogen bonds (Figure 3). In the (S,S,S,S)
tetramer 3, the amide bonds are orthogonal to the ring plane
and all point in the Same direction. In the (S,R,S,R)tetramer 4,
the orthogonal amide bonds alternatingly point in opposite directions. These cylindrical stacks display structural similarities
with the nanotubes investigated by Ghadiri et al.['] and by Sun
and ~ ~ ~ ~ ~ ~ i . [ 1 0 ]
Summarizing the structural results, one can say that P-peptides are at least as good candidates for protein folding as their
counterparts in the world of P-peptides. This fact raises the
following, thrilling question: what kinds of interactions exist
between the world of a-peptides and that of P-peptides? Seebach
et al. report that peptides composed of B-amino acids have not
yet been found to have mutagenic properties and that P-peptides
are stable against various peptidases." Another interesting
question with respect to P-peptides concerns the evolution of
life: why do we live in an a-peptide and not in a P-peptide world?
German version: Angew. Chem. 1997,109,1922-1923
Keywords: helical structures
protein structures
Figure 3. Side view of the solid-state structures of the cylindrical stacks made up of
the cyclopeptides 3 (left) and 4 (right). The intramolecular hydrogen bonds are
depicted in violet.
et al. attribute the stability of their 3,-helix to the conformationa1 rigidity of the cyclohexane rings.[41Van Gunsteren and Seebach et al. used molecular dynamics calculations to show that
the single stereogenic center in their /I-amino acids already causes a stable folding pattern. The 3,-helix, stable at 298 K, unfolds
Angew. Chem. Int. Ed. Engl. 1997,36, No. 17
hydrogen bonds
[I] D. Seebach, M. Overhand, F. N. M. Kiihnle, B. Martinoni, L. Oberer, U .
Hommel, H. Widmer, Helv. Chim. Acta 1996, 79, 913-941.
[2] D. Seebach, P. E. Ciceri, M. Overhand, B. Jaun, D. Rigo, L. Oberer, U. Hommel, R. Amstutz, H. Widmer, Helv. Chim. Acta 1996, 79, 2043-2066.
[3] T. Hintermann, D. Seebach, Synlett 1997, 437-438.
[4] D. H. Appella, L. A. Christianson, I. L. Karle, D. R. Powell, S. H. Gellman, J.
Am. Chem. Soc. 1996, f18, 13071-13072; B. L. Iverson, Nature 1997, 385,
[S] D. H. Apella, L. A. Christianson, D. A. Klein, D. R. Powell, X. Huang, J. J.
Barchi, Jr, S. H. Gellman, Nature 1997, 387, 381-384.
[6] Earlier investigations of possible elements of secondary structures in homopolymeric 8-peptides: F. Chen, G. Lepore, M. Goodman, Macromolecules
1974, 7, 779-783; H. Yuki, Y Okamoto, Y.Doi, .L Polym. Sci. Polym. Chem.
Ed. 1979, f 7 , 1911-1921; J. M. Fernandez-Santin, S. Munoz-Guerra, A.
Rodriguez-Galan, J. Aymami, J. Lloveras, J. A. Subirana, E. Giralt, M. Ptak,
Macromolecules 1987, 20, 62-68.
[7] X. Dauya, W F. van Gunsteren, D. Rigo, B. J a m , D. Seebach, Chem. Eur. J ,
3, 1410-1417.
[8] D. Seebach, J. L. Matthews, A. Meden, T. Wessels, C. Baerlocher, L. B. McCusker, Helv. Chim. Acta 1997,80, 173-182.
[9] J. D. Hartgerink, J. R. Granja, R. A. Milligan, M. R. Ghadiri, J. Am. Chem.
SOC.1996, 118,43.
[lo] X. Sun, G. P. Lorenzi, Helv. Chim. Acta 1994, 77, 1520.
[Ill T. Hintermann, D. Seebach, Chimia 1997, 51, 244.
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structure, secondary, shape, novem, taken, peptide
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