On the Role of Chirality in Guiding the Self-Assembly of Peptides

Article abstract of DOI:10.1002/anie.201706162

Homochirality in peptides is crucial in sustaining “like–like” intermolecular interactions that allow the formation of assemblies and aggregates and is ultimately responsible for the resulting material properties. With the help of a series of stereoisomer

Full text of DOI:10.1002/anie.201706162

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Accepted Article
Title: On the role of chirality guiding the self-assembly of peptides
Authors: Heinz-Bernhard Kraatz, Shibaji Basak, Ishwar Singh,
Annaleizle Ferranco, and Jebreil Syed
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Angewandte Chemie International Edition
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COMMUNICATION
On the role of chirality guiding the self-assembly of peptides
[
a]
[a]
[a]
[a]
[a] [b]
Shibaji Basak, Ishwar Singh, Annaleizle Ferranco, Jebreil Syed and Heinz-Bernhard Kraatz* ,
Abstract: Homochirality in peptides is crucial in sustaining “like-like”
intermolecular interactions that allow formation of assemblies and
aggregates, and ultimately is responsible for the resulting material
properties. With the help of a series of stereoisomers of the
tripeptide F-F-L, we can demonstrate the critical role that peptide
stereochemistry plays in the self-assembly of peptides, guided by
molecular recognition and for self-sorting. Homochiral self-
assemblies are stronger and more robust thermally and
mechanically
compared
to
heterochiral
self-assemblies.
Morphological studies of the multicomponent peptide systems
showed that aggregates formed from homochiral peptides
possessed a uniform nano-fibrous structure, while heterochiral
systems resulted in self-sorted systems of
a heterogeneous
morphology. In essence, homochiral peptides form the stronger
aggregate, which may be one of reasons why homochirality is
preferred in living systems.
Determining the enigma of the “Origin of life” is controversial and
scientists from all disciplines have made countless efforts to
solve this puzzle.[1] After the cooling of Earth’s surface, simple
organic molecules were derived from precursors as a result of
abundance, availability and chemical properties. Small organic
molecules further reacted to form a range of biopolymers,
including, nucleic acids and proteins, some of which are self-
replicating machineries, to initiate the first signature of life.
Recreating the prebiotic world in the laboratory to investigate
these very early reactions en route to Life is not trivial and have
required enormous approximations.[2-3] On the question of
chirality, it is surprising to notice that complex biopolymers, such
as proteins were comprise only of S-amino acids in most living
organisms.[4-5] The presence of homochirality and the lack of
racemic biological systems is a striking property that requires
proteins are biologically active building blocks for the
Figure 1. a) Chemical structures of stereoisomers of Ferrocene (1-8) and
Pyrene (9) appended tri-peptides. The chirality of each stereo-centre (i-iii) from
left to right has been followed to denote all compounds. b-f) Schematic
representation of self-assembly of homochiral organogelators into gel nano-
fibers. Homochiral Fc-based gelator 1 and 4 form non-fluorescent fibers
whereas 9 forms fluorescent fibers (upper panel). Mixing of 9 in the same pot
(both gelators are composed of S chiral centres) produced non-fluorescent
fibers, indicates a mixed stacking of peptide chains. However, mixing of
gelator 4 into 9 in the same pot (both the gelators are composed of opposite
chiral centres) results in fluorescent fibers, indicates self-sorted fiber formation.
Self-supportable organogels (in toluene at 10 mM concentration) obtained
from 1, 4 and 9, individually and in a two component fashion have been shown
beside each schematic self-assembly.
some investigation. There is evidence that homochirality is
required to create biopolymers with a function.[6-7] In this context,
Ghadiri and co-workers have reported that a polypeptide can act
as a replicator for homochiral products from a racemic mixture of
peptide fragments through a chiroselective autocatalytic cycle.[8]
This suggests that homochirality plays a critical role for structure
and function of such systems, including sustaining self-
replications cycles, however, chirality guided interactions
production of self-assembled nanostructures.[11-13] Peptides have
impressive molecular recognition abilities to distinguish between
its own kind exploiting a range of non-covalent interactions,
including hydrogen bonding, van der Waals forces, electrostatic,
between peptide molecules in the context of functionality are
rarely explored.[
9-10]
Peptide molecules that can mimic large
hydrophobic,
π-π
stacking
interactions
and
metal
coordination.[ Nowick and co-workers have reported that β-
sheet forming peptides strongly prefer homochiral pairing rather
than heterochiral pairing depending on hydrogen bonding and
peptide side chain interaction.[ Non-covalent interactions are
collectively strong enough and responsible to form highly
organized self-assembled 3D supramolecular structures with a
dynamic error correction property.[16-17] However, controlling the
self-assembly of a multicomponent system in one pot is rather
challenging.[18a] In contrast, Adams group reported self-sorting
behavior of two molecules by regulating the solution pH.[18b]
14]
[
[
a]
b]
Dr. S. Basak, I. Singh, A, Ferranco, J. Syed, Prof. Dr. H. -B. Kraatz
Department of Physical and Environmental Sciences
University of Toronto, 1265 Military Trail, Toronto, M1C 1A4
15]
(Canada)
E-mail: bernie.kraatz@utoronto.ca
Prof. Dr. H.-B. Kraatz
Department of Chemistry, University of Toronto
80 St. George Street, Toronto, Ontario M5S 3H6 (Canada)
Supporting information for this article is given via a link at the end of
the document.
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Marchesan group has reported the effect of chirality on self-
assembly using a series of tri-peptides in aqueous medium.[19]
Among all stereoisomers, different chirality in N-terminal formed
hydrogels. Interestingly, multicomponent gels where two or more
gelators are mixed together develop mixtures that have
properties completely different from the individual gels.[20] For
example, donor-acceptor co-gels composed of pi-functional
materials have remarkable opto-electronic properties.[20d-e] The
homochirality that exists in peptide chains is crucial in sustaining
organogels obtained from Fc-gelators and 9 (Figure 3a-c, S21a-
b). The homo/heterochiral organogels obtained from 1, 3, 4 and
6 were observed to have long fibers which showed three
dimensional - interweaving nano-architecture. In addition, the
calculated average diameters of thin fibers were 32(±5) nm,
41(±5) nm, 33(±6) nm and 34(±6) nm, respectively. Besides Fc-
gels, 9 shows three dimensional network morphology, but
average diameter was found to be 30(±4) nm which is thinner
than any Fc-gels.
“
like-like” molecular interaction in order to form co-
Frequency sweep rheology studies[32] were performed to
examine mechanical strength of these homo/heterochiral
organo-gels (Figure S24) at MGC (10 mM). The storage
modulus (G’) value of homochiral Fc-gels (1 : 4338 Pa and 4 :
assemblies.[ Chiral amino acids constitute the peptide chain,
encoded the bio-molecular information and direct the nano-
structure and physical property of resulting material.[21] Gaining
an understanding of why Nature promotes homochirality is
adding to our knowledge of early prebiotic systems and how life
may have benefited from homochirality. In this contribution, we
explore the role of chirality in peptides and how chirality affects
recognition of peptides and their self-assembly into larger
aggregates. For this purpose, we explore the self-assembly of
eight stereoisomers of a tripeptide Phe-Phe-Leu, 1-8 (Figure
20f]
3
3363 Pa) was found to be much higher (10 order) compared to
the heterochiral Fc-gels (3 : 114 Pa and 6 : 188 Pa) which
indicates homochiral Fc-gels are much stronger and stable than
the heterochiral Fc-gels. Organogel obtained from 9 showed
moderate gel strength (G’: 208 Pa). The metastability of
heterochiral Fc-gels (3 and 6) were measured in the form of tan
δ value (G’’/G’).[33] For 3 and 6, average tan δ value obtained
0.38 and 0.24, but for aged gels from the same sample showed
enhanced tan δ value as 0.99 and 0.61, respectively (Figure
S27) which confirmed the heterochiral gels lose its gelation
property with time. Organogels obtained from homochiral 1 and
4 are not only strong but also thixotropic in nature [ (Figure
S28), as shown by time dependent rheological studies (10 mM)
at a constant angular frequency of 10 rad/s. It was observed that
the G’ was higher than G’’ (loss modulus) in low strain step
(0.1 %) indicating gel phase whereas, at 100 % oscillatory strain
G’’ appeared higher than G’ indicating solution phase for both
the organogels obtained from 1 and 4. Therefore, homochiral
organogels have the ability to self-repair their gel network almost
immediately after removal of high oscillatory strain 100%.
Variable-temperature 1H NMR experiments (VT NMR) were
performed on all Fc-gels in toluene (Figure S30) from 20 to
60 °C (above Tgel).[22,28-29] It was observed that the position of
amide-proton signals of individual organogels shifted upfield as
the temperature approached to the Tgel. VT NMR studies for all
Fc-based organogels unambiguously support strong hydrogen
bonding interaction in gel state. The Tgel of organogel obtained
[
22]
1
a).
The inspiration for this tripeptide came from the central
part of the amyloid β-protein, in which the diphenylalanine motif
has a high tendency to self-assemble into larger aggregates.[23]
To facilitate our study, and enable us to monitor the molecular
recognition and the self-sorting, the tripeptides are labelled with
a ferrocene (Fc) group (1-8) and a pyrene (Py) group (9). Py is
highly fluorescent and the Fc tag serves as a fluorescence
quencher.[24] This combination allows us to examine self-
assembly of peptides and its dependence on chirality in a
multicomponent system. Our results clearly demonstrate the
critical role that peptide stereochemistry plays in the self-
assembly of peptides, guided by molecular recognition and self-
sorting.
Among all compounds, 1, 3, 4, 6 and 9 were found to form
self-supportable organogels[25-26] in toluene (Figure 1b-d and
Figure S20). The temperature required for the melting of self-
supportable gel (Tgel) range from 47-98 °C. In each case,
compounds were heated and cooled to room temperature
followed by ultra-sonication,[27] which produced self-supportable
organogels. Note that, ultra-sonication is not required for 9.
Detailed gelation behavior of molecules 1-9 in toluene have
been summarized in Table S1. Fc-Gels[28-29] obtained from 1, 3,
34]
1
from 9 is much higher than all Fc-based gels, therefore, H NMR
experiment does not provide any significant amide bond shift in
the experimental range.
4
and 6 were transparent and yellow in colour. In addition, the
gel obtained from Py-based peptide 9 was transparent and
colorless. However, though heterochiral gels 3 and 6 showed
transparent appearance initially, it started to become opaque
after 30-60 min with loss of solvent, indicating its metastable[30]
gelation ability (Figure S20b). Besides that, homochiral gels 1, 4
and 9 were stable and showed no change of state even after 24
hr. The metastable characteristic of heterochiral gels indicates
that homochirality is an important factor for stable organogel
formation. Initial organogel formation of heterochiral 3 and 6
could be attributed to the interaction of terminal homochiral
dipeptide fragment in each compound. The minimum gelation
concentration (MGC) for Fc-gels were found to be around 10
mM for 1, 3, 4 and 6. The MGC found to be 4 mM for 9 is
dramatically lower in concentration which could be due to the
additional π-π stacking ability of Py moiety.[31] However, other
heterochiral Fc-based peptides (2, 5, 7 and 8) produce solutions
in toluene and are incapable of forming any kind of gel after
prolonged ultra-sonication.
Molecular recognition is a process where a molecule
selectively recognizes and binds to another substrate molecule
by the help of various non-covalent interactions.[35] Specific non-
covalent interactions allows other molecules to interact with host
molecule in terms of size and shape.[7] To study the molecular
recognition phenomenon in our system, all homochiral and
heterochiral Fc-based peptides that formed organogels were
mixed individually with the homochiral Py-based compound, 9
(10 mM for each gelator).[36a] All Fc-based gelators (1, 3 and 6)
formed transparent co-gels with Py-based gelator 9 except 4,
which was translucent (Figure 2a). Note that, no sonication was
required for co-gel formation. The MGC were around 5 mM
(each gelator) for all co-gels, which are similar to compound 9.
However, the pyrene moiety is highly fluorescent and the gel
obtained from 9 shows bright blue fluorescence under the UV-
lamp illuminated at 365 nm (Fig. 2a, bottom panel).[36]
Interestingly, co-gel obtained from 9+4 shows strong
[
24]
fluorescence under UV lamp. Other co-gels obtained from 9+1,
9+3 and 9+6 show very weak fluorescence which is almost
negligible compared to 9. Fluorescence exhibited by 9 in gel
Transmission Electron microscopy (TEM) was carried out
to investigate the microscopic nano-structure of these
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state arises from the π-π stacking of Py moiety.[37] Non-
fluorescent behavior exhibited by co-gel 9+1 implies the
homochiral peptide chain of 9 (all S-chirality) forms mixed
stacking with peptide chain of 1 (all S-chirality) in a chirality
guided molecular recognition fashion (Figure S39). Therefore,
properties of Py moiety. The PL emission for co-gels obtained
form 9+1, 9+3 and 9+6 showed a signal at 397 nm followed by
another at 406 nm with a drastic decrease in PL intensity.
Compared to 9, there was a decrease in intensity of nearly 86 %
for co-gels 9+1, 9+3 and 9+6. The emission spectrum for co-gel
obtained from 9+4 differed from the other three co-gels; a peak
appeared at 388 nm followed by a shoulder at 406 nm.
Comparing the fluorescence intensity, it shows 63 % decrease
to 9. Concentration dependent PL spectroscopy (Figure 2c, S31)
was performed by gradual addition of each Fc-based gelator
dissolved in toluene (50 μL aliquot, 2 mM) to the toluene gel of 9
(10 mM). Heating-cooling cycle was performed after adding
each aliquot and fluorescence spectra were obtained
immediately after cooling. It was observed that all homochiral
and heterochiral co-gels showed the fluorescence intensity
decreased sharply after addition of each aliquot. The time
dependent PL spectroscopy (Figure 2d, S32) after a heat-cool
cycle was performed with the co-gel system (10 mM for each
gelator) and monitored for 24 hr. After formation it was observed
that, fluorescence intensity of all co-gels remained nearly
unchanged with respect to time, however; apart from co-gel
obtained from 9+4, where, fluorescence began to increase after
the Fc-moiety, which is
a strong fluorescence quencher,
interacts strongly with the π-surface of Py, and as
a
consequence of this interaction it leads to the disruption of the
aromatic-π stacking (Figure 1e and Figure S39). However, it is
surprising that 9 is capable of recognizing 3 and 6, which have
one and two identical chiral centers, respectively. In the peptide
chain of compound 4, all chiral centers are exactly opposite to 9.
Hence, the chirality of each center is completely mismatched
and presumably the side chain of each peptide hindered them to
form mixed stacking of peptide backbone (Figure S39).
Therefore, they form independent self-sorted fibers made of
stereogenically identical
15 min and became stable after 30 min. This indicates that the
self-sorting of individual fiber formation starts immediately after
gel formation and could be monitored by measuring Py
fluorescence. This study also supports, the homochiral peptide
chain of 9 can bind with the homochiral peptide chain of 1.
However, the interaction between 9 and 4, the molecular
recognition event differs to a certain degree as both of the
compounds possess exact opposite chiral centers.
Figure 2. a) Photograph of self-assembled organogel obtained from 9 and Co-
gels obtained from homo/heterochiral Fc-based peptides (1, 3, 4 and 6) in
presence of 9 in toluene (10 mM for each gelator).The appearance of co-gels
at day light (upper panel) and under UV lamp (365 nm, bottom panel) where 9
exhibits bright fluorescent emission but all co-gels show fluorescence
quenching except co-gel obtained from 9+4. b) PL emission spectra obtained
from 9 and all co-gels support the observed fluorescent behaviour showed by
co-gels. Spectra produced for 24 hr. aged gels. c) Concentration dependent
PL spectra show quenching of PL emission after gradual addition of Fc
peptides (1, 3, 4 and 6) into 9 (spectra were taken immediately after heating-
cooling cycle). d) Time dependent PL spectra after a heat-cool cycle show PL
emission increased only for co-gel obtained from 9+4 but other co-gels show
no response.
Figure 3. TEM images of organo-gels obtained from a) 1, b) 4 and c) 9, show
three dimensional fibrous network. d) TEM image of co-gel obtained from 9+1
shows uniform fiber morphology which supports the mixed stacking and
completely different from individual fibres obtained from 1 and 9. e-f), The
morphology of co-gel obtained from 9+4 shows two distinct morphology of
self-sorted fibers of two independent gelators. Concentration maintained 10
mM for each gelator. Images were taken from toluene gels after air drying.
Scale bars are 1 μm (a-f) and 2 μm (e).
molecules of individual gelators (Figure 1f, S39). It indicates the
homochiral stacking of individual molecule is favoured rather
than a heterochiral mixed stacking in a multicomponent system.
In the self-sorted fibers the Py stacking is not influenced by the
Fc moiety and ultimately shows fluorescence under UV lamp.
Thermal stability of these co-gels are quite difficult to measure
as they begin phase separation around 50°C keeping a gel like
mass which melts near Tgel of 9.
The molecular recognition and self-sorting phenomenon
can be unambiguously confirmed by the microscopic images
obtained from each co-gels. TEM imaging was performed by
taking samples from 24 hr. aged co-gels. The morphology
pattern changed dramatically, especially for co-gels where no
fluorescence was observed. Uniform thick bundles of tape like
fibers were observed for 9+1, 9+3 and 9+6 (Figure 3d and S34).
The average widths were found to be 43(±8) nm, 60 (±14) nm
and 43(±12) nm, individually. This indicates both molecules in
The molecular recognition and self-sorting property were
further confirmed by photoluminescence (PL) spectroscopy
(
monitored for 24 hr).[38] The emission spectrum of organogel
obtained from 9 at 10 mM concentration in toluene showed
strong emission around 409 nm followed by a shoulder around
436 nm (Figure 2b) which is consistent with the optical
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COMMUNICATION
co-gels are adhering to one another through the mutual
molecular recognition of the peptide residue in each molecule.
However, the morphology of the co-gel obtained from 9+4 was
remarkable and shows two distinct types of fibers (with widths of
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assembly. The multicomponent peptide systems showed that
chirality has an important role in recognition and aggregates
formed from homochiral peptides possess a uniform nano-
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[
Keywords: Peptides • Self-assembly • Gels • Molecular
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Angewandte Chemie International Edition
10.1002/anie.201706162
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Stereochemistry plays an important
role in the self-assembly of peptides,
guided by molecular recognition and
self-sorting. Homochiral peptides form
the stronger aggregate, which may be
one of reasons why homochirality is
preferred in living systems.
Shibaji Basak,[ Ishwar Singh,
Annaleizle Ferranco,[ Jebreil Syed
and Heinz-Bernhard Kraatz* ,
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On the role of chirality guiding the
self-assembly of peptides
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