Controlling curvature in a family of oligoamide α-helix mimetics

Article abstract of DOI:10.1002/anie.200803778

(Figure Presented) Catching up with the curve! The natural curvature found in a majority of a helices has been mimicked in small synthetic oligoamide scaffolds. Differences in hydrogen-bonding patterns in these scaffolds lead to mimetics with varying degrees of curvature in the backbone. This adds another parameter to the structural and functional mimicry of a helices.

Full text of DOI:10.1002/anie.200803778

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Chemie
DOI: 10.1002/anie.200803778
a-Helix Mimetics
Controlling Curvature in a Family of Oligoamide a-Helix Mimetics**
Ishu Saraogi, Christopher D. Incarvito, and Andrew D. Hamilton*
The structure of the a-helix was first proposed by Pauling and
Corey in 1951 and was subsequently found to be a common
motif in protein secondary structure.[1] As more structural
data on proteins became available, it was realized that the
idealized a-helix and b-sheet models proposed by Pauling are
often distorted. In optimizing their packing interactions, a
large percentage of a-helices curve or kink,[2,3] (Figure 1) and
b-sheets often deviate from planarity.[4] Kinks arising from
proline, for example, have been found to be conserved across
many species and may have a functional role.[5]
curved helices show a periodic shift in the amide proton
resonance that has been attributed to the varying degrees of
magnetic anisotropy of the peptide carbonyl group.[10]
Although such deviations in each residue are small and the
overall backbone geometry is maintained, the cumulative
effects along the helix make them significant. In seeking to
mimic the structure and function of a-helices in synthetic
scaffolds, it will be important to similarly reproduce different
degrees of curvature.
The synthetic mimicry, using non-natural oligomers, of
protein secondary structure and function has attracted con-
siderable interest over the last two decades.[11] A recent
advance in this area is the characterization of higher-order
assemblies of these structures.[12] We have reported synthetic
a-helix analogues[13] that mimic the recognition properties of
residues at positions i, i + 3 (and/or i + 4), and i + 7 of the helix
and successfully disrupt key protein–protein interactions.[14–16]
One such family of scaffolds is based on an aryl amino acid
oligomer in which intramolecular hydrogen bonds maintain
the integrity of the structure (Scheme 1). When the aryl ring is
Figure 1. a) A straight helix and b) a curved helix in granulyte colony-
stimulating factor (PDB ID: 1BGC); c) the two helices in (a) and (b)
superimposed to highlight the curvature in the helix in (b); d) A kinked
helix in lysin (PDB ID: 1LIS); adapted from Kumar et al.[6]
A survey of the protein data bank has shown that the a-
helix backbone can be classified as linear, curved, or kinked,
with a majority of a-helical domains showing a smooth
curvature with a radius of less than 100 ꢀ.[3,6–8] These
deviations from the idealized linear form result from dis-
tortions in peptide-bond geometry and, in the case of
amphipathic helices, from variations in the hydrogen-bonding
patterns in the hydrophobic core versus the hydrophilic
exterior.[8,9] Curvature has a significant bearing on the
packing interactions, dipole moments, and spectroscopic
properties of a-helices.[3,8] For example, the NMR spectra of
Scheme 1. Oligoamides used in this study: a) dimers and b) trimers.
pyridine, a curvature is seen and the direction of side-chain
projection is affected.[15,16] This curvature in the solid-state
structure appears to come from the geometrical restraints
imposed by the hydrogen bond from the pyridine nitrogen
atom to the amide -NH group. We reasoned that removing the
hydrogen bond and introducing additional steric crowding
through the use of a benzene ring in place of the pyridine ring
would cause a straightening of the molecule and a decrease in
the curvature of the backbone. In this way we would have a
simple means of controlling the curvature.
[*] I. Saraogi, Dr. C. D. Incarvito, Prof. A. D. Hamilton
Department of Chemistry, Yale University
225 Prospect Street, P.O. Box 208107
New Haven, CT 06520-8107 (USA)
Fax: (+1)203-432-6144
E-mail: andrew.hamilton@yale.edu
[**] We thank the National Institutes of Health (GM69850) for financial
support of this work.
A systematic search for arylcarboxamide-based structures
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200803778.
in the Cambridge Structural Database (CSD)[17] revealed that
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the hydrogen-bonding characteristics of the molecule had a
significant effect on the angle at which the two aryl rings are
inclined to each other (Figure 2). The degree of inclination
A superimposition of the X-ray crystal structures of the
oligobenzamide dimer 1 (red) and oligopyridylamide dimer 2
(blue) shows the diminished curvature in 1 (Figure 3). The
Figure 2. Some representative structures from the CSD showing differ-
ent angles of inclination of the aryl rings; CSD Refcode: a) WOYVAH,
b) GEPQIC, c) ACALAR, and d) SAQKEA; non-NH hydrogen atoms
have been omitted for clarity; red O, blue N, green C, white H, light
green Cl; the angle of inclination as defined in this study is shown as
inset.
Figure 3. X-ray crystal structures of 1 (a) and 2 (b) showing the
relevant angles; the two structures have been superimposed (c) to
show the difference in curvature (red 1, blue 2). The nitrogen atoms in
the pyridine rings are in light blue. Non-NH hydrogen atoms and tBu
ester groups in 1 have been omitted for clarity; red O, blue N, green
C, white H.
was defined as the angle at which the carbon atom of the aryl
ring bound to the amide -NH group is inclined to the line
connecting carbon atoms 1 and 4 of the preceding aryl ring
(Figure 2, inset). Molecules with a N-phenylpicolinamide
substructure have a relatively smaller angle of inclination
presumably because of greater distortion of the pyridyl–
amide bond angle to accommodate the hydrogen bond
(Figure 2a,b). In N-phenylbenzamides, where no intramolec-
ular hydrogen bonding is possible, the two rings can rotate
two pyridine rings in 2 are tilted at an angle of 152.08 to each
other, compared to 159.98 in 1. As a consequence of the
hydrogen bonding, the geometry of the amide bond is more
distorted in 1 as evidenced by the H-N-Caryl bond angle, which
is significantly smaller (1078) than the ideal amide bond angle
of 1208. The corresponding angle in the pyridine analogue is
=
À
À
=
more freely about the C( O) aryl and N(H) aryl bonds. In
this case, the angle of the tilt is larger (Figure 2c). This is also
true when an o-hydroxy group is present, as in our proposed
molecules (Figure 2d). The larger angle of inclination com-
pared to the phenylpicolinamides implies that longer oligom-
ers of N-phenyl-p-benzamide will be straighter, that is, they
will have a smaller overall backbone curvature.[18]
1208. The N-C-C( O) bond angle in 2 (116.28) is much smaller
than that in the benzene counterpart (123.08) to allow for the
bifurcated hydrogen bonds to form. A similar trend is also
seen in the C-C-Osidechain angles, which are smaller in cases
where hydrogen bonding takes place. The additive effect of
these amide bond distortions leads to a significantly greater
curvature in 2 relative to 1.
Based on this information from the CSD, we first
synthesized the dimeric arylcarboxamide analogues of these
mimetics containing benzene (1) and pyridine (2) groups
(Scheme 1a). The syntheses of these and their longer
homologues (see below) were straightforward and involved
an iterative acyl chloride coupling and nitro-group reduction
protocol of the appropriate pyridine and benzene monomers
(see the Supporting Information). Support for the presence of
the second hydrogen bond to the pyridine ring comes from
NMR studies showing the amide proton in 2, which partic-
ipates in bifurcated hydrogen bonding, to be shifted signifi-
cantly downfield compared to that in 1, which forms only a
single hydrogen bond to the alkoxy group (Table 1).
The effects of the hydrogen bonding and consequently the
curvature should be more pronounced in trimers 3–6
(Scheme 1b) because of an accumulation of these effects. In
analogy with the above dimers, the oligobenzamide com-
pound 3 is expected to be less curved than the oligopyridy-
lamide compound 4. Molecules 5 and 6, with mixed oligopyr-
idylamide and oligobenzamide backbones, should lie in
between the two extremes. This hypothesis was supported
by molecular modeling and energy minimization studies of
trimers 3–6 using the consistent value force fields (CVFF)
within InsightII (Figure 4).
An iterative strategy similar to that for the dimers was
used to synthesize molecules 3, 4,[16] 5, and 6 (see the
Supporting Information). As with the dimers, the peaks in the
NMR spectra for both the amide protons in 4, but only one
proton in both 5 and 6, appear at lower field strengths
compared to the amide protons in 3 (Table 1).
Table 1: NMR shifts of the amide proton in molecules 1–6.
Compound
d
Compound
d1
d2
The X-ray crystal structures of 3, 4,[16] 5, and 6 (Figure 5)
confirmed the predicted trend in backbone curvature and the
bond angles followed a trend similar to the dimers. The N-C-
[ppm]
[ppm]
[ppm]
1[a]
2[b]
9.64
10.22
3[a]
9.45
10.12
8.85
9.71
10.25
10.36
10.57
4[16][b]
5[a]
=
C( O) bond angle in the case of benzene rings was found to
6[a]
9.46
be approximately 1248 while the same angle was much smaller
( ꢀ 115–1178) in the case of pyridine rings where bifurcated
NMR solvents used:[a] CDCl3; [b] [D6]DMSO.
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Chemie
hydrogen bonding occurs. In 3, the angles at which the
aromatic rings are tilted to each other are 161.28 and 160.98,
while in 4 the same angles are 152.48 and 151.18. In 5, where
the top half of the molecule closely resembles 3, this angle is
159.38 while the bottom half is similar to 4 with an angle of
152.48. As expected, these numbers are reversed for 6 with
values of 151.28 and 160.38 respectively. Thus, molecules 5 and
6 have an overall curvature that lies between that of 3, which
is least curved, and that of 4, which is most curved.
In conclusion, we have shown that our oligoarylamide a-
helix mimetics adopt a curved backbone structure in analogy
to the majority of a-helices found in protein crystal structures.
The curvature can be tuned by modifying the hydrogen-
bonding characteristics of these simple compounds through
the choice of appropriate building blocks, that is, by switching
from phenyl to pyridine rings. This approach adds to the
repertoire of tools available for the effective mimicry of
protein secondary structures by choosing a scaffold that most
closely mimics the a-helix of interest.
Figure 4. Superimposed stereoview representation of the acid deriva-
tives of trimers 3–6 obtained from modeling in InsightII (red 3, blue 4,
green 5, purple 6). Only the oxygen atom of the sidechains has been
shown for clarity.
Received: August 1, 2008
Revised: September 17, 2008
Published online: November 6, 2008
Keywords: curvature · helical structures · hydrogen bonds ·
.
oligoamides · proteomimetics
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