Sheet-forming abiotic hetero foldamers

Article abstract of DOI:10.1039/b713229h

Abiotic hetero oligomers, adopting a well-defined extended self-assembled sheet-like structure, derived from conformationally constrained aliphatic and aromatic amino acid residues repeating at regular intervals are reported. The Royal Society of Chemistr

Full text of DOI:10.1039/b713229h

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Sheet-forming abiotic hetero foldamers{
Pranjal K. Baruah,a Naduthottiyil K. Sreedevi,a Baisakhi Majumdar,b Renu Pasricha,b Pankaj Poddar,b
Rajesh Gonnade,b Sapna Ravindranathanc and Gangadhar J. Sanjayan*a
Received (in Cambridge, UK) 29th August 2007, Accepted 27th November 2007
First published as an Advance Article on the web 14th December 2007
DOI: 10.1039/b713229h
morphological architecture of the large hexadecapeptide foldamer
4 shows fibril piles composed of entangled nanofibrils, a
morphological signature of extensive self-assembly,9 which is also
substantiated by the results of crystal structure studies (vide infra).
The foldamers, derived from conformationally constrained Aib
and 3-amino-5-bromo-2-methoxy benzoic acid (Amb)3i residues
(Aib–Amb motif 1), were designed anticipating that the corre-
sponding oligomers 2, 3, and 4 would adopt a well-defined,
compact, three dimensional structure, governed by a combined
conformational restriction imposed by the constrained Aib and
Amb residues.
Abiotic hetero oligomers, adopting a well-defined extended self-
assembled sheet-like structure, derived from conformationally
constrained aliphatic and aromatic amino acid residues
repeating at regular intervals are reported.
Foldamers1 as a class of conformationally ordered synthetic
oligomers have moved into prominence primarily due to their
enormous potential for the creation of unnatural oligomers adopt-
ing conformational features, akin to biopolymers. Investigations
by several groups have resulted in the generation of several such
synthetic oligomers with diverse backbone structures and con-
formations.2 Of late, increasing attention has been given to the
exploration of abiotic aromatic foldamers that display novel
functions, properties and conformational features, as has been
independently demonstrated by various research groups.3 An out-
standing example is the development of a foldamer, by Hamilton’s
group, that exerts a strong influence on the shape of growing
calcite crystals via specific interactions between the functional
groups attached to the foldamer and the newly expressed faces of
the growing calcite crystals.3a The self-assembling hetero foldamers
developed by Gong’s group4 could find profound application in
the development of supramolecular polymers; polymers formed
exclusively from non-covalent interactions.5
Whereas the achiral Aib residue is known to play a key role10 in
the conformational restriction of polypeptides due to its over-
whelmingly constrained phi (w ¡ 60u) and psi (y ¡ 30u) torsion
Herein we describe a novel class of abiotic hetero foldamers
derived from conformationally constrained amino acids, both
aliphatic and aromatic, repeating at regular intervals (Fig. 1). The
striking feature of these a-aminoisobutyric acid (Aib)-rich synthetic
hetero oligomers is their ability to form self-assembled sheet-like
structures through extensive intermolecular hydrogen bonding
interactions from the backbone amide groups; an observation that
is in stark contrast to the general finding that Aib is proven as a
sheet breaking amino acid, at least in oligomers composed of
a-amino acids.6,7 It is noteworthy that sheet forming structural
architectures have implications in the understanding and develop-
ment of potential therapies for Alzheimer’s disease, a leading cause
of dementia in the elderly, which is pathologically defined by the
occurrence of amyloid plaques, composed of the amyloid
b-protein, and neurofibrillary tangles.8 Indeed, scanning of the
aDivision of Organic Synthesis, National Chemical Laboratory, Dr.
Homi Bhabha Road, Pune 411 008, India.
E-mail: gj.sanjayan@ncl.res.in; Fax: (+91) 020-25893153;
Tel: (+91) 020-25902082
bCentral Material Characterization Division, National Chemical
Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India
cCentral NMR Facility, National Chemical Laboratory, Dr. Homi
Bhabha Road, Pune 411 008, India
{ Electronic supplementary information (ESI) available: Full experimental
procedures, 1H NMR, 13C NMR, and ESI mass spectra of all new
compounds. See DOI: 10.1039/b713229h
Fig. 1 Molecular structure of dipeptide 1, tetrapeptide 2, octapeptide 3,
and hexadecapeptide 4 foldamers synthesized in this study.
712 | Chem. Commun., 2008, 712–714
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angles, the backbone-rigidified aromatic amino acid residue Amb
and its analogs2c are known to induce a crescent conformation in
its oligomers via localized S(5) and S(6) type11 hydrogen bonding
interactions. Thus, we reasoned that hetero-oligomers made of
Aib–Amb repeat motifs might also display conformational rigidity;
which was indeed realized, as evident from structural investigations
(vide infra). The bromine atoms on the periphery of the aromatic
nuclei in the foldamers were meant to aid crystallization and to
improve the quality of crystal data, due to the presence of heavy
bromine atoms.12 It is noteworthy that one of the biggest
challenges in the structural investigation of large synthetic
oligomers is their resistance to yield to crystal formation.
backbone, as expected, with w and y torsion angles of the central
Aib residue close to 52u.
This effect was also noted in our previously reported hetero
foldamers containing Aib residues.14 Detailed analysis of the
crystal structure further revealed self-assembly of the individual
strands of the oligomer 2. The self-complementary individual
strands of 2 undergo self-assembly through intermolecular
…
N–H OLC hydrogen bonding interactions, with an average
…
˚
D–H A length: 2.251 A, to afford an extended sheet-like
structure, an observation that could provide insights for develop-
ing such templates into potential protein-b-sheet mimetics.2b It is
noteworthy that an extended sheet structure has been disclosed
…
The Aib–Amb motif-based foldamers 2–4 were assembled from
N3–Aib–Amb–OMe building block 1, using a segment doubling
strategy (experimental details in the ESI{). Curiously enough, all
efforts to couple BOC–Aib–OH with H–Amb–OMe were
unsuccessful, under a variety of coupling conditions, which
prompted us to use the azide moiety as the masked amine
surrogate. The solubility profiles of the oligomers in non-polar
solvents were noted to progressively deteriorate with an increase in
size of the oligomer, a fact that is presumably due to extensive
aggregation in higher order oligomers. This fact is also vindicated
by the results of investigation of the oligomers 2–4 by transmission
electron microscopy (TEM), (vide infra). It is noteworthy that an
increasing tendency of oligomers to self-aggregate is known to be
recently in certain cyclopropane c-peptides stabilized by C–H O
hydrogen bonds,15 and also in isotactic acrylamide oligomers.13
The extended conformation of the individual strands, as noted
in the crystal structure of 2, is prevalent in solution-state as well, as
evidenced from 2D NOESY NMR studies of the oligomers 2 and
3 (Fig. 3).
However, the poor solubility of the hexadecapeptide foldamer 4,
presumably due to extensive aggregation (self-assembly), rendered
its conformational studies by solution-state NMR spectroscopy
difficult. One of the most characteristic NOE interactions that can
be anticipated for an extended conformation, as seen in the crystal
structure of 2, would be the requirement of sequential dipolar
couplings between the protons of adjacent residues of Aib–Me,
Ar–NH, Ar–OMe, and Aib–NHs. Such a sequential interaction is
clearly observed for both tetrapeptide 2 and octapeptide 3,
suggesting an extended conformation for the individual strands,
similar to the one observed for 2 in its crystal structure (observed
paralleled by
a
decrease in their solubility profile.13 The
hexadecapeptide foldamer 4 was only sparingly soluble in
DMSO. Due to this reason, the synthesis of oligomers larger than
the hexadecapeptide foldamer 4 could not be undertaken.
Among the oligomers, the tetrapeptide foldamer 2 crystallized
from methanol in monoclinic space group P21/c,{ although the
higher order oligomers did not yield crystals suitable for single
crystal X-ray studies, despite best efforts. Investigation of the
crystal structure of 2 (Fig. 2) revealed that the intrinsically
constrained Aib residues imposed significant twist on the foldamer
Fig. 2 Crystal structure of foldamer 2 (top, ball and stick representation)
and its H-bond-mediated self-assembled structure (bottom, capped stick
representation). Hydrogens, other than at the hydrogen bonding sites,
have been omitted for clarity.
Fig. 3 Partial 2D NOESY spectra of 2 (top) and 3 (bottom) showing
characteristic NOEs. For enabling assignments, the molecular structure
with selected numbered atoms are also shown. The dipolar couplings are
indicated with red dotted arrows.
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architectures of these oligomers further suggest their potential in
fabricating novel supramolecular nanoarchitectures.
PKB is thankful to CSIR, New Delhi, for a Senior Research
Fellowship. This work was funded partly by the International
Foundation for Science (IFS), Sweden; Grant No. F/4193-1, and
the Department of Science and Technology (DST), New Delhi.
Fig. 4 (A), (B), and (C): TEM images of the oligomers 2, 3, and 4,
respectively, deposited on carbon coated polymer film. Corresponding
selected area electron diffraction (SAED) patterns are shown in the inset.
Note: Full-size figures are available in the ESI (S25, S26).{
Notes and references
{ Crystallographic data of 2: CCDC 640754. For crystallographic data in
CIF or other electronic format see DOI: 10.1039/b713229h
NOEs for 2: Aib1 vs. NH1 vs. OMe1 vs. NH2 vs. Aib2 vs. NH3 vs.
OMe2). Further, we also note a characteristic dipolar coupling
between the NHs of adjacent residues (S24, ESI{) in both 2 and 3.
Indeed, closer inspection of the crystal structure of 2 reveals the
close proximity of NHs of adjacent residues in the extended
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˚
conformation (d: 2.8 A). In order to provide insights into the
hydrogen-bonding interactions in solution, we also performed
[D6]DMSO titration studies on the oligomer 3 (details in ESI,
S27{). The titration results reveal that all the NHs show downfield
shifts upon increasing the concentration of [D6]DMSO (from 0 to
50 mL), suggesting their role in intermolecular interactions. The
effect is particularly pronounced for all the Aib NHs of the
octapeptide 3 (Dd y 1 ppm).
To investigate the morphological architecture and its effect on
the length of the oligomer, we analyzed the self-assembled
structures by TEM. Fig. 4A, B, and C show the TEM images of
the oligomers 2, 3, and 4, respectively, deposited on carbon coated
polymer film.
Comparison of the photomicrographs of the oligomers:
tetrameric foldamer 2 vs. octamer 3 vs. hexadecamer 4, reveals
an interesting structural aspect. As the oligomer size increases, the
morphological architecture transforms from crystalline needle
shape (Fig. 4A) to entangled nanofibrils (Fig. 4C). In the case of
the tetrameric foldamer 2, the particles are needle shaped and are
flat, as evident from the Mo`ire pattern seen from the overlapping
of two needle shaped nanoparticles (indicated by an arrow in
Fig. 4A). Further, the particles of 2 with size #400 nm are
crystalline in nature as shown by the SAED pattern in the inset
(Fig. 4A). In the case of octamer 3, the size of the particle is #3 mm
and the SAED pattern shown in the inset (Fig. 4B) is diffused,
indicating a loss in the crystalline structure. However, the
microscopic image of the hexadecamer foldamer 4 (Fig. 4C)
reveals fibril piles composed of entangled nanofibrils, a morpho-
logical signature of extensive self-assembly.9
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In summary, we have developed novel synthetic oligomers that
adopt well-defined, compact, three-dimensional architectures,
governed by a combined conformational restriction imposed by
the individual amino acid constituents. The notable feature of
these Aib-rich synthetic oligomers is their ability to form self-
assembled sheet-like structures through extensive intermolecular
hydrogen bonding interactions from the backbone amide groups,
an observation that is in stark contrast to the general observation
that Aib is proven as a sheet breaking amino acid, at least in
oligomers composed of a-amino acids.6 Therefore, these results
suggest the utility of the hybrid foldamer strategy in modulating
conformational preferences of individual amino acids in oligomer
sequences. The results of investigation of the morphological
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714 | Chem. Commun., 2008, 712–714
This journal is ß The Royal Society of Chemistry 2008