Based on these highly specific molecular zippers or glues, a systematic approach to designing self-assembled structures is now feasible.. By specifyingintramolecular noncovalent interacti
Trang 1R E V I E W A R T I C L E
Well-defined secondary structures
Information-storing molecular duplexes and helical foldamers based on unnatural peptide backbones
Adam R Sanford, Kazuhiro Yamato, Xiaowu Yang, Lihua Yuan, Yaohua Han and Bing Gong
Department of Chemistry, University at Buffalo, State University of New York, Buffalo, NY, USA
Molecules and assemblies of molecules with well-defined
secondary structures have been designed and characterized
by controllingnoncovalent interactions By specifying
intermolecular interactions, a class of information-storing
molecular duplexes have been successfully developed These
H-bonded molecular duplexes demonstrate programmable,
sequence-specificity and predictable, tunable stabilities
Based on these highly specific molecular zippers (or glues),
a systematic approach to designing self-assembled structures
is now feasible Duplex-directed formation of b-sheets,
block copolymers and templated organic reactions have
been realized By specifyingintramolecular noncovalent
interactions, a backbone-rigidification strategy has been
established, leadingto unnatural molecular strands that
adopt well-defined, crescent or helical conformations The generality of this backbone-rigidification strategy has been demonstrated in three different classes of unnatural oligomers: oligoaramides, oligoureas and oligo(phenylene ethynylenes) Large nanosized cavities have been created based on the foldingof these helical foldamers Tuningthe size of the nanocavities has been achieved without changing the underlyinghelical topology These helical foldamers can serve as novel platforms for the systematic design of nano-structures
Keywords: backbone rigidification; duplex; foldamer; folding; helix; hydrogen bond; nanocavity; noncovalent; self-assembly; template
Introduction
The assembly and foldingof biomolecules are arguably two
of the most important features in nature There is no doubt
that without the ability of nature to form very stable
aggregates of small molecules, or to form well-defined
secondary, tertiary and even quaternary structures of
macromolecules, life could not exist as we know it For
example, the formation of duplex DNA represents one of
the most elegant and best known examples of both
self-assembly and foldingof biomacromolecules [1] The folding
of polypeptide chains into secondary and eventually a
bewilderingarray of tertiary structures results in protein
molecules that are responsible for most of the biological
interactions and functions found in nature
A logical next step is to mimic nature and create
nonbiologically derived molecules that either fold into
well-defined secondary structures, or assemble into larger
architectures Since the early 1990s there has been a great
deal of literature devoted to these types of biomimetic
structures that involve intermolecular self-assembly and/or
intramolecular foldingof unnatural molecules, and their potential applications [2–15] The focus of a growing number of research groups including our own is to achieve structures whose properties may lead to multitudes of applications both in and out of the biological realm The development of most of the unnatural assemblingand foldingstructures has been inspired by peptide and protein structures For example, the pioneeringstudies of Gellman and Seebach on b-peptides, a class of unnatural peptidomi-mimetic foldingoligomers, have demonstrated the feasibility
of foldingunnatural oligomers into well-defined conforma-tions Extendingthe concept of b-peptides has led to other peptidomimetic foldamers such c-peptides [16,17], d-pep-tides [18,19] and oxa-pepd-pep-tides [20] The early investigation on molecular association of nucleobases by Jorgensen and Zimmerman has led to the development of highly specific H-bonded pairs that have been used in specifyinginter-molecular interactions [21–23] Although there has been a great deal of work in both molecular self-assembly and folding, the focus of this review primarily covers the work completed and ongoing in our laboratory For a more com-prehensive view of these two fields there have been a number
of excellent reviews published in recent years concerning molecular self-assembly and folding[2–15,25–29,39]
Hydrogen-bonded duplexes
Nature has, of course, a monopoly on the most complex self-assemblies of molecules In nature, the cooperative action of many noncovalent attractions often leads to highly specific recognition events, resulting in thermodynamically stable assemblies The unfavorable loss in entropy is usually
Correspondence to B Gong, Department of Chemistry, 811 Natural
Sciences Complex, University at Buffalo, State University of New
York, Buffalo, NY 14260, USA.
Fax: + 1 716 6456963, Tel.: + 1 716 6456800 ext 2243,
E-mail: bgong@chem.buffalo.edu
Abbreviations: A, acceptor; D, donor; m-PE, oligo(meta-phenylene
ethynylene).
(Received 17 December 2003, revised 6 February 2004,
accepted 2 March 2004)
Trang 2digital fashion [2] Modules with high specificity and strength,
when tethered to various structural components, can serve as
information carriers for instructingthe formation of a variety
of self-assemblingstructures Compared to systems whose
assembly depends directly on the structural features of the
correspondingmolecular components, such an approach
is more versatile because structural units that are either
incompatible or only randomly associate with one another
can now be forced to assemble The correspondingmodules
thus act as templates for organizing and assembling structural
components in specific sequential and spatial arrangements
A great majority of the modules have used the hydrogen bond
as the primary stabilizingforce due to the predictable
directionality and strength of this noncovalent interaction
Duringthe last decade, hydrogen-bonded complexes
based on rigid heterocycles with multiple H-bonding donor
(D) and acceptor (A) sites have received the most attention
as recognition modules [2] Systems based on various
H-bonded modules have been reported For example,
Whitesides et al described multicomponent structures
based on the cyanuric acid–melamine motif [24–26] The
groups of Zimmerman [30–32] and Meijer [33–35] reported
heterocyclic complexes with arrays of H-bond donors
and acceptors Krische [36] and Hunter [37] developed
H-bonded duplexes Ghadiri et al [38,39] reported the
assembly of modified cyclic peptides utilizingeight
hydro-gen-bonds while Rebek et al reported on the assembly of
curved monomers that assembled into a form reminiscent of
a tennis ball [40,41]
In spite of their increasingly wide applications, the use of
heterocycle-based modules may suffer from several
compli-cations Most heterocyclic systems are accompanied by
tautomerism [30], resultingin loss of information and
reduction of the observed association constants In addition,
one must consider that in heterocycle-based modules,
secondary electrostatic interactions, due to the proximity
of adjacent H-bond donors and acceptors, often complicate
the predictability of the strength of the designed complexes
We have developed our own approach for designing
molecular recognition modules using molecular duplexes
that are not only sequence-specific, but also with
program-mable sequences and tunable stabilities [3]
Molecular duplexes: programmable, information-storing
molecules
We recently developed a class of highly stable molecular
duplexes that are characterized by their by
sequence-specificity and tunable stability: one single strand carrying
an arrangement (sequence) of H-bond donors and acceptors
specifically recognize another strand with a corresponding
complementary H-bondingsequence (Fig 1) [3] These
duplexes adopt an extended, tape-like conformation The
H-bondingsequences of these duplexes are readily
programmable Single strands with almost any donor– acceptor arrangement can be designed and prepared based
on straightforward amide/peptide chemistry These duplexes also showed regio-specificity and can thus act as molecular manipulators
Specifically, the molecular strands involve oligoamides consistingof meta-substituted benzene rings linked by glycine residues The amide O and H atoms act as H-bond donor and acceptor sites Various arrangements of the amide O and H atoms lead to Ôhydrogen bonding sequencesÕ that allow the specific association of two single strands carryingcomplementary seqences [3]
The structure of a six-H-bonded duplex is shown in Fig 2
to illustrate the specific design: the duplex consists of two identical oligoamide strands carrying self-complementary H-bondingarrays of AADADD Connectingthe aromatic buildingblocks with glycine linkers in different order leads
to oligoamide strands carrying different arrays (sequences)
of H-bond donors and acceptors As a result, duplexes with both self-complementary and complementary H-bonding sequences have been designed and characterized Our study has demonstrated that these molecular duplexes are char-acterized by predictable, tunable affinity, programmable sequence-specificity and convenient synthetic availability, makingthem ideal as recognition modules for the instructed assembly of various structural units
Four H-bonded duplexes [3,42] The first generation duplexes were designed around a four-H-bond platform with self-complementary H-bondingsequences of DDAA and DADA (Fig 3) Of note are the six-membered inter-molecular hydrogen bonds that not only serve to block any undesirable intermolecular H-bond interactions, but also force a molecular conformation conducive to dimerization Dimerization for both complexes was studied and confirmed through 1D, 2D and variable temperature
(molecular zipper).
Fig 2 A six-H-bonded, self-complementaryduplex.
Trang 3NMR experiments, and vapor pressure osmometry studies.
Association constants between these homodimers were
determined based on concentration-dependent chemical
shifts of the amide protons The dimerization constant for
the DADA homodimer was found to be > 4.4· 104M )1
while the dimerization constant for the DDAA dimer was
found to be 6.5 · 104
M )1 The amino acid linker showed very little effect on the
strength of the dimerization as a whole For example, when
the glycine used in initial tests was replaced with a bulkier
phenylalanine, the dimerization constant was found to be
4 · 104
M )1, within the ±10% error associated with the
NMR method used in determiningthe constant All three
types of compounds, regardless of D–A sequence and
amino acid spacer, exhibit very similar association constants
and can be considered to have roughly the same stabilities
This is in contrast to H-bonded complexes based on rigid
heterocycles, whose stabilities are influenced by secondary
electrostatic interactions and are thus not only determined
by the number of H-bonds, but also depend on the specific
arrangement of the H-bond donors and acceptors The
sequence-independent stabilities of our duplexes are easily
explained by the larger distance (>5 A˚) between their
adjacent intermolecular H-bonds than those (<2.3 A˚) of
the H-bonded pairs of rigid heterocycles Thus, by adjusting
the number of intermolecular H-bonds, the stability of a
duplex can be controlled accordingly
For example, compared to the four-H-bonded duplexes,
the dimerization constant of a two-H-bondingmolecule was
found to be dramatically lower ( 25M )1) [42] Thus, if the
number of H-bond D/A sites is increased, the overall
stability of the correspondingduplex should also increase
This led to the investigation of even longer, more complex
duplexes The investigations also focussed on the creation of
duplexes of consistingof two different but complementary
strands
Six H-bonded Duplexes [3,43] The next step in the
course of investigation involved six-H-bonded molecular
duplexes Initially, compounds 1 and 2 were designed and
synthesized as complementary pairs with only one allowable
mode of dimerization (Fig 4) Initial indications of
dime-rization were apparent as the solubilities of separate
solutions of 1 (< 1 mM) and 2 ( 10 mM) were low but
that of the 1 : 1 mixture of the two in the same solvent was
much higher ( >>100 mM) This phenomenon
presuma-bly was due to the shieldingof the highly polar amide
groups on the Ôsticky edgeÕ of each single strand
The formation of the six-H-bonded duplex was
conclu-sively confirmed by 2D NMR data showingcritical
interstrand NOEs in chloroform In addition, the duplex
could even be detected by straight phase (SiO2) TLC Using10% dimethylformamide in chloroform as the eluant, differences in Rf values between 1 (Rf¼ 0.00),
2 (Rf¼ 0.10) and the 1 : 1 mixture (Rf¼ 0.96) clearly indicated the formation and high stability of the duplex Further NMR studies showed significant downfield shifts
of the amide protons of the 1 : 1 mixture of 1 and 2
in comparison to the separate solutions of the single strands Attempts to determine the dimerization constant by NMR failed as no upfield shift of the amide protons was detected upon dilution in CHCl3to a concentration as low as 1 lM Isothermal titration calorimetry was employed to deter-mine the association constant via titration of 1 with 2
in chloroform The result can only be estimated to
be¼ 1 · 109M )1in chloroform, in agreement with NMR results A more accurate value of Kawas determined when the titration was carried out in chloroform containing5% dimethyl sulfoxide, resultingin an association constant of 3.5· 106M )1
In addition to the above complementary pairs of duplexes, a self-complementary, six-H-bonded duplex were also studied (see Fig 2) Again, as with other six-H-bonded duplex, NMR experiments failed to determine an associ-ation constant due to the high strength of the associassoci-ation
By assuminga 10% dissociation, a lower limit of 4.5· 107
M )1was estimated for the Ka Interstrand NOEs were observed under a wide range of concentration conditions, indicatinglittle dissociation even in highly dilute solution Simple observation on a TLC plate indica-ted even greater stability than that of a similar non-self-complementary six-H-bond duplex Virtually no tailing, indicative of dissociation, was observed on the TLC medium for the self-complementary duplex while the non-self-complementary strand showed significant tailing To determine a more accurate association constant, a pyrene-labeled derivative of this self-complementary system was studied by a fluorescence method The dimerization con-stant was determined to be (6.8 ± 4.1)· 109
M )1 Such a strongstability and the feature of self-complementarity gives this compound an interesting potential for the synthesis of supramolecular, high molecular mass homo-polymers [44]
The sequence-specificity of the six-H-bond duplex was probed with the inclusion of mismatched bindingsites along the backbone of a duplex (Fig 5) [45] This study provided a unique look at the importance of sequence-specificity on these unnatural self-assembly systems The mismatched pairs were studied with 1D and 2D NMR and isothermal titration calorimetry The results were compared to the
Fig 3 Self-complmentary, four-H-bonded duplexes.
Fig 4 Example of six-H-bond, complementaryduplex 1•2.
Trang 4parent complementary duplex The ÔmismatchedÕ strands
still assemble as do the ÔmatchedÕ strands, but with much less
stability Isothermal titration calorimetry experiments
revealed that the mismatched duplexes exhibited stabilities
40 times less than that of the correspondingmatched pairs
Duplex foldamers [46]
Progress with our four- and six-H-bonding duplexes led to
the development of a new class of compounds with eight
H-bondingsites Single strands 4 and 5, one with two
DDAD modules and the other with two AADA modules
linked in a head-on fashion, were originally designed to
form supramolecular polymers Similarly, a
self-comple-mentary strand consistingof two ADAD modules linked
head-to-head was also designed If these strands adopted an
extended conformation, the directionality of the
unsym-metrical four-H-bond module would enforce a partial
overlap of the molecular strands, leadingto the formation
of supramolecular polymers Instead, it was discovered that
each eight-H-bonding strand associated with one separate
complementary strand; however, like many
biomacromole-cules, the molecular strands adopted a well-defined, folded
conformation (Fig 6)
strands, may serve as templates to bringthe peptide strands into close proximity In addition, the programmable sequence-specificity of the duplexes allows the design of unsymmetrical H-bondingsequences, which ensures the precise registration of the amino acid residues of the attached natural peptide strands, leadingto the formation
of two-stranded b-sheets Therefore, the organizational stability of the H-bonded duplexes provided an opportunity for nucleatingand stabilizingb-sheets, a feature that could help provide critical insight into such structures As opposed
to studies on b-sheets based on b-hairpins, the nature of such an assembly is intermolecular, makingit possible to pair peptides of various lengths and sequences by simply mixingthe correspondingtemplated peptides (Fig 7) The resultant mixingof complementary hybrid duplex strands would force the otherwise flexible peptide chains to form b-sheets
To evaluate the strategy of nucleation and stabilization of b-sheets, we designed four hybrid chains, each consisting
of a tripeptide segment coupled with a region capable of forminga four-H-bonded duplex (Fig 8) The H-bonding sequence of the duplex was designed to be unsymmetrical to direct the peptide chains to the same (or different) end of the template Hybrids 6a and 6b were paired with hybrids 7a and 7b
As a control, hybrid 6c was designed Pairing 6c to the correspondinghybrid strands led to the attachment of the tripeptide chains to the opposite end of the duplex template
H1NMR results of duplexes of 6a with 7a and 7b, as well
as 6b with 7a and 7b exhibited very sharp, well-defined resonances indicative of well-defined overall structures Mixtures of 6c with its correspondingpartner showed no such resolution, exhibitingbroad, nearly indistinguishable resonances Also observed was the noticeable chemical shift
of the H1 NMR resonances in only the complementary hybrid strands in comparison to single hybrid strands and the tripeptide strands alone
Two-dimensional NMR (NOESY) studies provided conclusive evidence of duplex and b-sheet formation NOE contacts were observed between opposite amino acid residues In the case of ‘plain’ tripeptide mixtures or duplexes with ‘wrongly’ attached tripeptides, no NOE contacts were observed
Fig 5 An example of a duplex containing a mismatched ‘binding’ site.
Fig 6 Single strands 4 and 5 Each strand consistingof two identical
four-H-bondinghalves linked in a head-on fashion, were originally
designed to (A) form supramolecular polymer, but were found to (B)
adopt folded (stacked) conformations upon associatingwith each
other.
Fig 7 Schematic representation of b-sheet nucleation and stabilization bya four H-bond duplex template.
Trang 5Further investigations based on H-bonded duplexes
Supramolecular block copolymers The extraordinary
spe-cificity and stability of our H-bonded duplex is again
demonstrated recently in the design of supramolecular
block copolymers By attachingthree polystyrene and three
poly(ethylene glycol) chains to the two strands of a duplex
derived from 1 and 2, a total of nine block coploymers were
created by simply mixingthe polymer-tethered templates
(Fig 9) NOESY study confirmed that the duplex template
was precisely matched as expected from the H-bonding
sequences The successful noncovalent linkingof the
polystyrene and poly(ethylene glycol) chains was confirmed
by size exclusion chromatography More exciting were the
results from the atomic force microscopy that revealed
microphase separation typical of covalent block copolymers
by these supramolecular block copolymers Figure 9B shows one such atomic force microscopy image of a pair carryingpolystyrene 21 000 and poly(ethylene glycol) 6000 chains
A duplex-templated organic reaction Olefin metathesis reactions have found applications in a wide variety of fields [48,49] Intermolecular olefin meta-thesis involvingtwo different olefins can be complicated by the fact that a mixture of three products can result when the two reactingolefins have similar stabilities The use of our duplex strands can solve this problem By tetheringtwo separate olefins on two complementary strands, the olefins
Fig 8 Hybrid duplex strands.
Fig 9 Block copolymers (A) Design of supramolecular block copolymers based on the six-H-bonded hetero-duplex 1•2 Mixingthree templated polystyrene chains with three complementarily templated poly(ethylene glycol) chains leads to nine block copolymers (B) The AFM image showing microphase separation of one of the supramolecular block copolymers.
Trang 6Intramolecular self-assembly: helical
foldamers
In recent years there has been intense interest in creating
oligomers and/or polymers with unnatural backbones that
display stable, well-defined conformations Pioneering
reports from Gellman [7,50] and Seebach [51,52] on
helically folding b-peptides opened the floodgates for a
rush of reports on other unnatural helical structures
From the c-peptides reported by Hanessian [53] and
Seebach to the oligo(pyridine dicarboxamides) reported
by Huc and Lehn [54] to the foldingoligo(m-phenylene
ethynylenes) reported by Moore [55,56] and the helical
aromatic oligoureas by Tanatani [57], folding structures
are obviously not monopolized by nature itself We have
reported novel helical foldamers based on the enforced
folding of oligoarylamides and oligo(phenylene
ethyny-lenes) that exhibit well defined helical secondary structures
that have great potential in both materials science and
biological application
Oligoamide foldamers
Our approach to the design of helical foldamers involves
the development of oligoarylamides with rigid, crescent
backbones [58,59] These oligoamides can also be viewed
as aromatic c-peptides The initial focus was placed on
oligomers consisting of building blocks derived from
2,4-dihydroxy-5-nitrobenzoic acid (or meta-disubstituted
buildingblock) When derivatives of this molecule were
connected via an amide bond, it was reasoned that the
bifurcated (three-centered) H-bond, consistingof the two
intramolecularly H-bonded five and six membered rings,
would limit the rotational freedom of the aryl-amide bonds
The three-centered H-bonds rigidify the overall backbone
and thus force a crescent shape, for example, on the
tetramer shown in Fig 10 The resulting three-centered
hydrogen bond was found to be highly stable from both
theoretical and experimental evidence [59]
The crescent and/or helical conformations should be
reinforced by the interplay of multiple factors such as the
state and in solution From this data it is clear that the orientation of the amide oxygens yielded an interior cavity that is electronegative and hydrophilic Once the conforma-tion of the amide backbone was confirmed, the extension of the backbone beyond the length of a single turn, and thus a helix was attempted [60]
Indeed, combiningtwo tetramers with a symmetrical residue derived from 4,6-dihydroxyisophthalic acid, resulted
in nonamers of more than one full helical turn [60] Side chains, however, were found to play a critical role in the solubility of the correspondingoligomers It was found that oligomers carrying short side chains such as methyl or isopropyl groups had rather limited solubility Long alkyl chains, such as the linear octyl or dodecyl groups, were adopted to impart solubility However, it was discovered that when side chains longer than a methyl group were placed on adjacent residues of an oligomer, this led to a distortion/twistingof the helix, primarily from steric inter-actions between side chains This problem was solved by designing oligomers containing methyl side chains on every other residue Recently, a buildingblock carryingone long alkyl and one methyl side chain became available, making
it possible to construct oligomers using a single building block
The folded structures were rigorously characterized by both 2D and X-ray crystallography The helices show excellent stability in organic solvents and our recent results show that foldingalso occurred in very polar (and hydrogen bond disrupting) solvents such as water and dimethyl sulfoxide The persistence of the highly favorable three-centered H-bonds, which act to rigidify the backbone and lead to the overall folded conformations of the oligoamides, was further demonstrated by extremely slow amide proton– deuterium exchange rates
While in nature, large cavities of nanometer scale are usually found at the tertiary or quarternary structural level
of proteins, we have been able to create and tune the nanocavities while maintainingthe same helical topology of our foldamers [60] One of the highly attractive features of our system is the relative ease in which the interior cavity
Fig 10 A tetrameric crescent oligoamide (A) and its crystal structure (B) For clarity, the octyl groups are replaced with green dummy atoms in the crystal structure.
Trang 7can be altered It was initially envisioned that by merely
incorporatinga certain proportion of residues derived from
2,3-hydroxy-4-nitrobenzoic acid (or simply
para-disubsti-tuted buildingblock) into the oligomer, the curvature of the
correspondingbackbone would be decreased, leadingto an
increase in the size of the interior cavity (Fig 11) For
example, a 21-mer (Fig 12) consisting of alternating
meta-and para-buildingblocks was found to fold into a helical
conformation of slightly more than one spiral turn The
existence of a helical conformation was supported by
end-to-end NOEs and by NOEs between each amide proton
and the protons on two of its neighboring side chains
A computer model of the 21-mer constructed based on
parameters from the X-ray structures of short oligomers of
the same system revealed a helix with an interior cavity of
over 30 A˚ across, the largest thus far created by unnatural
foldamers [60]
Extension of this porous foldamer system beyond our
original explorations is at the forefront of our current focus
As indicated by NMR and X-ray crystallographic data, the
interior channel lined by amide oxygens has potential for
application Short oligomers may act as membrane-bound
carriers for ions and small molecules; longer oligomers may fold into nanotubes with hydrophilic channels Oligomers with lengths matching the thickness of the lipid bilayer could act as channels for transportingions and small molecules (Fig 13) The side chains, which point radially outward on the exterior of a helix, should help the integration of our porous foldamers into lipid bilayers
Probingthe stability of our backbone-rigidified helical foldamers in polar solvents will be one of our future studies Oligomers that fold stably in aqueous media are
of great interest due to their biological significance and their potential for the development a variety of bio-related materials The incorporation of triethylene glycol side chains and aliphatic chains terminated with carboxyl groups are the strategies we intend to use to render the correspondingoligomers reasonably soluble in aqueous media
If an oligoamide backbone could fold into well-defined and robust conformation based on backbone rigidification, could the same strategy of backbone rigidification be applied to different unnatural backbones? Initial work in our laboratory involvingoligoureas have shown promise
Fig 11 Adjusting cavitysize bytuning the curvature of a backbone.
Fig 12 A 21mer (approximatelyhalf is shown) with an interior cavity
of > 30 A˚.
Fig 13 Schematic representation of ion channel based on our porous helix.
Trang 8Folding oligoureas
The backbones of this class of oligomers involve benzene
rings linked by N,N¢-disubstituted urea groups (Fig 14)
The presence of ester groups ortho to the urea N atoms leads
to the formation of a intramolecularly H-bonded,
six-memberd ring, which, combined with the preferred (cis, cis)
conformation of the urea group, leads to the rigidification of
the oligourea backbone The meta-disubstituted benzene
rings, in combination with the nonlinear urea groups,
enforce a curved conformation Molecular modelingstudies
showed that, for oligomers with more than four residues, a
helical conformation results (Fig 14A) The interior of the
helix is characterized by oxygen atoms from the urea
functionality, which lead to hydrophilic cavities of 4 A˚
across Urea linkages have the advantage of being
chem-ically robust and resistant to most natural enzymes
In contrast to the large cavity of the crescent oligoamides
mentioned above, the much smaller sizes of the neutral,
electrostatically negative cavities of the oligoureas are ideal
for bindingand/or transportingions Our ultimate goal is to
develop these foldamers into novel ion carriers, and
eventually, into ion channels Oligoureas from the dimer
to the hexamer have been prepared Extensive studies based
a residue with an ether group results in five-membered hydrogen-bonded rings The backbone of the corresponding oligomer should be more flexible due to the weaker H-bond
in the five-membered ring
The drivingforces that facilitate the foldingof these oligoureas are virtually identical to those for the folding of oligoamides mentioned above: (a) two localized intramole-cular hydrogen bonds that lead to the rigidification of each
of the cis, cis-urea linkages and (b) the aromatic stacking interaction that further stabilized the helical conformation Folding oligo(phenylene ethynylenes) [62]
The strategy of backbone rigidification has also been also applied to oligo(meta-phenylene ethynylenes) (m-PEs) Solvent-driven foldingof oligophenylacetylenes carrying
Fig 14 Folding oligourea (general structures).
Fig 15 A backbone-rigidified hexa (phenylene ethynylenes).
Fig 16 Tuning the cavityof backbone-rigidified m-PE foldamers A larger cavity can be produced by incorporating one (left) or two (right) para substituted residues.
Trang 9polar side chains has been well established by Moore and
coworkers [56,57] The Moore system relied on polar side
chains to effect a hydrophobic collapse of the PE backbone,
leadingto helical structures that were denatured in nonpolar
solvents Based on the m-PE system, a completely different
foldingstrategy was achieved by introducingan
intra-molecular H-bond that restrict the rotational freedom of
the backbone (Fig 15)
Folded m-PE oligomers, from dimers to heptamers, were
observed in nonpolar solvents such as chloroform The
folded conformations were confirmed by X-ray and
2D-NMR studies As anticipated, the 2D 1H NMR
(NOESY) spectrum of a hexamer showed end-to-end NOEs
that could only be explained by a helical confirmation of this
oligomer Similar to the crescent oligoamides, the cavity size
of the backbone-rigidified m-PEs can be tuned by changing
the connectivity of some of the backbone units (Fig 16)
Placingthe H-bonds and the correspondingside chains
inward should lead to functional cavities
Conclusions
While progress has been made in mimicking the basic
features of biological systems, there is still a great deal of
work to be done For all intents and purposes, molecular
self-assembly and molecular foldingare still in their
infancy Nearly all unnatural systems, while elegant and
fascinatingin their own regard, still fall well short of
the shear complexity and grandeur of constructs seen in
nature The recognition, interaction and folding of
bio-molecules, particularly biomacrobio-molecules, have inspired
most of the currently known unnatural systems By
mimickingnatural systems, the scientific community has
witnessed the breathtakingprogress made the relevant
fields over the past decade The advantage of unnatural
systems, however, is not limited to mimickingthe
structures and functions of biological molecules The
potential of unnatural self-assemblingor foldingmolecules
may ultimately lie with the scientists, who are only limited
by their imagination
Alongthese lines of thinking, we have succeeded in
synthesizingand characterizingnovel, and potentially useful
self-assembly and foldingsystems that draw inspirations
from nature, which may be applied to both natural and
unnatural settings Both our information-storing duplexes
and helical foldamers have already shown
excitingpoten-tials in a variety of different applications, and are motivating
us toward the development of new systems
Acknowledgements
We thank the NASA (NAG5-8785), NSF (CHE-0314577), NIH
(R01G M 63223), ONR (N000140210519) and ACS-PRF (37200-AC4)
for financial support.
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