β-Sheet to Helical-Sheet Evolution Induced by Topochemical Polymerization: Cross-α-Amyloid-like Packing in a Pseudoprotein with Gly-Phe-Gly Repeats

Article abstract of DOI:10.1002/anie.201914975

Protein-mimics are of great interest for their structure, stability, and properties. We are interested in the synthesis of protein-mimics containing triazole linkages as peptide-bond surrogate by topochemical azide-alkyne cycloaddition (TAAC) polymerization of azide- and alkyne-modified peptides. The rationally designed dipeptide N₃-CH₂CO-Phe-NHCH₂CCH (1) crystallized in a parallel β-sheet arrangement and are head-to-tail aligned in a direction perpendicular to the β-sheet-direction. Upon heating, crystals of 1 underwent single-crystal-to-single-crystal polymerization forming a triazole-linked pseudoprotein with Gly-Phe-Gly repeats. During TAAC polymerization, the pseudoprotein evolved as helical chains. These helical chains are laterally assembled by backbone hydrogen bonding in a direction perpendicular to the helical axis to form helical sheets. This interesting helical-sheet orientation in the crystal resembles the cross-α-amyloids, where α-helices are arranged laterally as sheets.

Full text of DOI:10.1002/anie.201914975

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Accepted Article
Title: β-Sheet to Helical-sheet Evolution Induced by Topochemical
Polymerization: Cross-α-amyloid-like Packing in a Pseudoprotein
with Gly-Phe-Gly Repeats
Authors: Kana M Sureshan and Kuntrapakam Hema
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201914975
Angew. Chem. 10.1002/ange.201914975
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10.1002/anie.201914975
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COMMUNICATION
β-Sheet to Helical-sheet Evolution Induced by Topochemical
Polymerization: Cross-α-amyloid-like Packing in a Pseudoprotein
with Gly-Phe-Gly Repeats
Kuntrapakam Hema, and Kana M. Sureshan*
Abstract: Protein-mimics are of great interest in the contexts of their
structure, stability and properties. We are interested in the synthesis
of protein-mimics containing triazole linkage as peptide-bond
surrogate via topochemical azide-alkyne cycloaddition (TAAC)
polymerization of azide-and-alkyne-modified peptides. The rationally
designed dipeptide N3-CH2CO-Phe-NHCH2CCH (1) crystallized such
that the molecules are arranged in β-sheet arrangement in one
direction and in head-to-tail fashion in perpendicular direction. Upon
heating, crystals of
1 underwent single-crystal-to-single-crystal
polymerization forming triazole-linked pseudoprotein having Gly-Phe-
Gly repeats. Though the dipeptide adopted β-sheet-like alignment, the
pseudoprotein has evolved into a helix as a consequence of TAAC
polymerization. These helical pseudoprotein chains are laterally
assembled via backbone H-bonding in a direction perpendicular to the
helical axis to form helical sheets. This interesting helical-sheet
orientation in crystal resembles the interesting cross-α-amyloids,
where a-helical proteins are arranged laterally as sheets. This is the
first example of a pseudoprotein mimicking this interesting topology.
Self-assembly of proteins/peptides to form higher order structures
is an essential process for imparting biological functions to these
biomolecules.1 Tubulin polymerization,2 oligomerisation of
porins,3 two-dimensional arraying of bacteriorhodopsin,4
fibrillation of structural proteins such as myosin,5 collagen6 and
actins,7 are representative biological processes that exemplify the
importance of protein self-assembly. A common mode of self-
assembly for many proteins and peptides is the formation of
amyloids, which contain multiple copies of the protein arranged to
form fibrils. The common amyloids have the cross-b arrangement,
wherein b-strands run in a direction perpendicular to the fibril axis
and they stack via hydrogen bond along the fibril axis.8 Recently,
for the first time, an amyloid fibril with a cross-a arrangement has
been reported for the 22-residue peptide (PSMa3), a key
virulence factor secreted by Staphylococcus aureus.9 In this fibril,
a-helices run in a direction perpendicular to the fibril axis and they
are stacked in the direction of fibril axis through attractive
interaction between side chains (Figure 1a). Zhang et al. have
designed small peptides that self-assemble in cross-a amyloid-
like structures forming twisted spirals and has been characterized
using single crystal X-ray diffraction (SCXRD) analysis.10
Figure 1. (a) Cartoon representations of PSMα3. (b) Supramolecular helical-
sheets. (c) Covalent helical-sheets.
Recently, a supramolecular helix formed by head-to-tail assembly
of a tripeptide showing this arrangement has been reported by
Bera et al. (Figure 1b).11 Interestingly, in this case, the
(supramolecular) helices are connected laterally via H-bonding
between amide groups of the peptide backbone as in b-sheets,
giving this assembly the structural features of both helix and b-
sheet (helical-sheet, Figure 1b). Mondal et al. have designed a
heptapeptide that adopted cross-a alignment in crystals, which
transforms to thermodynamically stable cross-b fibrils when
heated.12 Here we report the first example of helical-sheet (cross-
a-amyloid-like) structure of a covalent pseudoprotein (Figure 1c)
formed via single-crystal-to-single-crystal (SCSC) polymerization
of a dipeptide monomer.
[*]
K. Hema, Prof. Dr. K. M. Sureshan
School of Chemistry
Indian Institute of Science Education and Research
Thiruvananthapuram
Kerala-695551 (India)
E-mail: kms@iisertvm.ac.in
Homepage: http://kms514.wixsite.com/kmsgroup
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Figure 2. (a) Chemical structure and ORTEP diagram of 1 (Ellipsoids are shown at 30% probability). (b) Hydrogen bonding pattern in 1 showing parallel β-sheet
alignment of molecules in the crystallographic a-direction. (c) Non-covalent molecular chains arranged in head-to-tail fashion through C-H…N hydrogen bonds
connecting molecules from two adjacent ‘bc’ planes (wavy arrow) and C-H…π hydrogen bonds (straight arrow) connecting molecules from same ‘bc’ plane along
b-direction. (d) Parallel orientation of azide and alkyne showing favourable distance for the cycloaddition reaction between molecules of two adjacent ‘bc’ planes.
(e) Parallel orientation of azide and alkyne showing large distance between reactive groups of adjacent molecules of same ‘bc’ plane.
Topochemical reactions are controlled by the molecular pre-
organization in the crystal lattice.13 Various photochemical14 and
thermal15 topochemical reactions have been reported. Some well-
known polymerizations that happen under topochemical control
include [2+2]16 and [4+4]17 cycloaddition polymerizations,
polymerization of dienes,18 trienes,19 diynes,20 triynes,21
quinodimethanes22 and N-carboxyanhydrides.23 We have been
interested in topochemical azide-alkyne cycloaddition (TAAC)
reaction, the lattice-controlled cycloaddition reaction between
proximally placed azide and alkyne groups giving triazole
products in the crystals.24 We have exploited this reaction for
synthesizing several biopolymer-mimics wherein the small
biomolecule-based monomers are linked via triazolyl-linkages.25
Along these lines, we have planned to synthesize novel
pseudoprotein having Gly-Phe-Gly repeats using the dipeptide 1.
The guiding principles for such a design are the β-sheet packing
of dipeptides containing Phe-Gly units26 and the consistent
proximal alignment of C-terminal and N-terminal substituents
between adjacent stacks of β-sheet forming peptides in their
crystals.27
We synthesized the azide-and-alkyne-substituted dipeptide 1
(Figure 2a and Supporting Information, Figure S1) and
crystallized it from a mixture of methanol and toluene (1:1 v/v) as
colorless needles. SCXRD analysis revealed that the dipeptide
crystallized in monoclinic space group (P21) with a single
molecule in the asymmetric unit. As expected, this dipeptide
adopted β-sheet packing along crystallographic ‘a’ direction via N-
H…O hydrogen bonding and other supplementary weak
hydrogen bonding interactions between adjacent molecules
(Figure 2b and Table S2, Supporting Information). Molecules are
connected in head-to-tail fashion along ‘b’ direction via CH…N
and CH…π hydrogen bonds (Figure 2c). While the CH…π
hydrogen bond connects molecules from the same ‘bc’ plane
(pink arrow), the CH…N hydrogen bond connects molecules from
adjacent ‘bc’ planes in an alternate manner as shown as the wavy
sky blue arrow (Figure 2c). Despite this head-to-tail alignment of
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molecules along crystallographic ‘b’ direction, the azide and
alkyne groups are neither proximally placed (average distance
5.13 Å) nor in a ready-to-react parallel orientation (angle 93.6°).
However, voids are present near the alkyne and azide (Figure S2,
Supporting Information), which might allow these reactive groups
to rotate around their conformationally flexible linkages and in this
process, they can transiently attain a reactive parallel orientation
(transition-state like alignment). Parallel orientation can be
attained between the molecules connected by CH…π hydrogen
bond (molecules of the same ‘bc’ plane) and between the
molecules connected by CH...N hydrogen bond (molecules of the
adjacent ‘bc’ planes). In order to analyze the possibility of the
TAAC reaction, we have rotated these reactive groups using
GaussView 5 to make them parallel to each other. When the azide
and the alkyne are parallel to each other, the average distance
between them is 5.29 Å if they are from the same ‘bc’ plane and
3.57 Å when they are from the adjacent ‘bc’ planes (Figures 2d &
2e). This suggests that the reaction is favored between molecules
of adjacent ‘bc’ planes along ‘b’ direction, and the polymerization
would propagate along the CH...N hydrogen bonded non-covalent
chains described earlier.
Figure 3. (a) Chemical structure and ORTEP diagram of 2 (ellipsoids are shown at 30% probability). (b) Helicity in the pseudoprotein 2 (view along the screw axis
of helix; phenylalanine side groups are omitted for clarity). (c) Helical triazole-linked pseudoprotein formation along b-direction. (d) Hydrogen bonding pattern in 2
showing the conserved sheet arrangement along a-direction (phenylalanine side groups are omitted for clarity).
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To investigate the topochemical reactivity, the crystals were
heated at 60 C and small fractions were withdrawn at different
(Figure S3c and Figure S7, Supporting Information) and we were
able to solve the crystal structure of the pseudoprotein (Figure 3).
Though the space group was retained, significant changes were
observed in the unit cell parameters. While the parameters ‘a’ and
‘c’ increased by 2.3% and 10.3% respectively, the parameter ‘b’
has decreased by 10.4%. The polymerization happened along the
crystallographic b-direction as anticipated (Figure 3c), which
accounts for the reduction in the unit cell parameter ‘b’. An overlay
of the crystal structures of dipeptide and pseudoprotein (Figure
S8, Supporting Information) suggested that both the azide and
alkyne units rotated to attain a reactive parallel orientation as
anticipated.
Interestingly, the pseudoprotein adopted a left-handed helical
conformation in crystal with b-axis as its screw axis (Figure 3b).
This left-handed helicity is in contrast to the right-handed helicity
commonly found in a-helices of natural proteins. While a-helices
have 3.6 amino acid residues per turn with a pitch of 5.4 Å, the
helices in pseudoprotein 2 have six amino acid residues with a
pitch of 15.0 Å. Though a-helices are stabilized by intrahelical H-
bonding (each ith residue makes H-bond with i+4th residue), no
attractive intrahelical interaction other than a CH…O hydrogen
bond (between para-H of Phe to the C=O of 5th Gly residue) is
present in our case. Interestingly, along a-direction (perpendicular
to the helical axis) the helical chains are connected by N-H…O
hydrogen bonds, similar to the dipeptide, forming sheet of the
helical chains (helical sheet; Figure 3d). This helical-sheet is
stabilized by various intermolecular hydrogen bonds between two
adjacent helices. There are two NH…O H-bonds, one CH…O H-
bond and one CH…π H-bond between two repeating units of
adjacent pseudoprotein chains (Table S2, Supporting
Information). As anticipated, the TAAC reaction has progressed
along b direction by connecting the molecules of two adjacent ‘bc’
planes alternatively (Figure 4).
o
time of heating for various time-dependent studies. Each of these
samples were analyzed by 1H NMR spectroscopy, IR
spectroscopy, powder X-ray diffraction (PXRD) and differential
scanning calorimetry (DSC). Time-dependent 1H NMR study
suggested that the reaction started within two days of heating as
was evident from the gradual appearance of signals due to
triazole product and the concomitant reduction of signals due to
the dipeptide (Figure S3a, Supporting Information). The reaction
was complete in 9 days giving the pseudoprotein containing Gly-
Phe-Gly repeats connected by triazolyl linkage. The reaction
occurred regiospecifically (Figure 3a) to form the 1,4-disubstituted
triazolyl linked pseudoprotein exclusively, as was confirmed by
various NMR spectroscopic techniques (Supporting Information.
Section 13). This regiospecificity confirms the topochemical
control of the reaction. The time-dependent IR spectroscopy
showed the gradual disappearance of the azide stretching signal
at 2104 cm-1 due to the gradual consumption of azide in the
cycloaddition reaction (Figure S3b, Supporting Information).
Time-dependent PXRD studies revealed that the sample showed
sharp diffraction peaks at every stage of the reaction and this
confirms that the crystallinity was maintained during the reaction
(Figure S3c, Supporting Information). By using MALDI-TOF
analysis, polymer chains comprising of up to 81 aminoacids could
be detected (Figure S4, Supporting Information). Gel permeation
chromatography (GPC) analysis revealed that the polymers
formed have an average molecular mass of 19053 and a
polydispersity index of 1.15 (Figure S5, Supporting Information).
The considerable mosaicity present in the crystals may be
influencing the chain length of the polymer (Figure S6, Supporting
Information).
Interestingly, the crystallinity and morphology of the heated
crystals remained intact even after compete polymerization
Figure 4. Schematic representation of helical-sheets formation in the pseudoprotein crystals induced by TAAC reaction.
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We have compared the solid state circular dichroism (CD) spectra
of pseudoprotein with that of dipeptide. While the monomer
(dipeptide 1) showed only the characteristic signature for β-sheet
like packing with a positive cotton effect at 230 nm, the polymer
(pseudoprotein 2) exhibited typical signatures for both helical
alignment and β-sheet-like arrangement showing a negative
cotton effect at 255 nm and a positive cotton effect at 227 nm
(Figure 5a). The CD spectrum of the pseudoprotein in solution
clearly showed the distinctive features of random coil alignment.
Thus CD studies confirmed that the helicity is present only in the
as-formed crystalline state and is induced by virtue of the TAAC
reaction but is not an inherent feature of the polymer. The thermal
stability of the crystalline (helical sheet) and amorphous (random)
forms of the pseudoprotein were analysed by thermogravimetric
analysis (TGA). In crystals, the pseudoprotein is stable up to 290
backbone hydrogen bonding. Designed dipeptide having azide
and alkyne groups at its termini crystallized such that the
molecules are arranged in β-sheet arrangement and the
molecules between adjacent β-sheet stacks are aligned in head-
to-tail arrangement. Though the azide and alkyne groups were not
in a ready-to-react parallel orientation, upon heating the crystals,
these reactive groups attained a transient reactive conformation
through rotational motion and then reacted regiospecifically via
TAAC reaction to form triazole-linked pseudoprotein in SCSC
fashion. As the TAAC reaction connected molecules from two
adjacent planes alternatively, the pseudoprotein formed attained
helicity and without compromising the H-bonded β-sheet
assembly. This is the first report on the helical-sheet topology of
a large pseudoprotein.
oC, whereas the
amorphous pseudoprotein
showed
decomposition from 150 oC onwards (Figure 5b). The higher
stability of the crystalline pseudoprotein could be accredited to its
ordered helical sheet packing.
Acknowledgements
KMS thanks Science and Engineering Research Board, India and
Department of Science and Technology, India for a research grant
and SwarnaJayanti Fellowship. We thank Dr. Subhrajyoti
Bhandary for fruitful discussions.
Keywords: Click reaction • helical sheet • pseudoprotein •
topochemical reaction • polymerization
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A designed dipeptide having azide
and alkyne groups at its termini
adopts β-sheet packing in its crystal
and undergoes single-crystal-to-
single-crystal polymerization via
topochemical azide-alkyne
Kuntrapakam Hema, Kana M.
Sureshan*
Page No. – Page No.
β-Sheet to Helical-sheet Evolution
Induced by Topochemical
cycloaddition reaction to evolve into a
pseudoprotein having interesting
helical-sheet packing in its crystals.
This helical-sheet orientation in the
pseudoprotein crystal resembles the
novel cross-α-amyloids, wherein α-
helical protein assembles laterally.
Polymerization: Cross-α-amyloid-like
Packing in a Pseudoprotein with Gly-
Phe-Gly Repeats
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