Complex Cascade Reaction Networks via Cross β Amyloid Nanotubes

Article abstract of DOI:10.1002/anie.202011454

Biocatalytic reaction networks integrate complex cascade transformations via spatial localization of multiple enzymes confined within the cellular milieu. Inspired by nature's ingenuity, we demonstrate that short peptide-based cross-β amyloid nanotubular hybrids can promote different kinds of cascade reactions, from simple two-step, to multistep, to complex convergent cascades. The compartmentalizing ability of paracrystalline cross-β phases was utilized to colocalize sarcosine oxidase (SOX) and hemin as an artificial peroxidase. Further, the catalytic potential of the amyloid nanotubes with ordered arrays of imidazoles were used as hydrolase mimic. The SOX-hemin amyloid nanohybrids featuring a single extant enzyme could integrate different logic networks to access complex digital designs with the help of three concatenated AND gates and biologically relevant stimuli as inputs.

Full text of DOI:10.1002/anie.202011454

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Accepted Article
Title: Complex Cascade Reaction Networks via Cross β
Amyloid Nanotubes
Authors: Chiranjit Mahato, Ayan Chatterjee, and Dibyendu Das
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Complex Cascade Reaction Networks via Cross β Amyloid
Nanotubes
Ayan Chatterjee,† Chiranjit Mahato† and Dibyendu Das*[a]
Abstract: Biocatalytic reaction networks integrate complex cascade
transformations via spatial localization of multiple enzymes confined
within the cellular milieu. Inspired by Nature’s ingenuity, we
demonstrate that short peptide based cross-β amyloid nanotubular
hybrids can promote different kinds of cascade reactions, from simple
two-step, multistep to complex convergent cascades. The
compartmentalizing ability of paracrystalline cross-β phases was
utilized to colocalize sarcosine oxidase (SOX) and hemin as artificial
peroxidase. Further, the catalytic potential of the amyloid nanotubes
with ordered arrays of imidazoles were used as hydrolase mimic. The
designed SOX-hemin amyloid nanohybrids featuring a single extant
enzyme could integrate different logic networks to access complex
digital designs with the help of three concatenated AND gates and
biologically relevant stimuli as inputs.
convergent cascades (Figure 1). Further, we demonstrate the
generation of complex bio-computed logic systems that used
multiple inputs and three-concatenated AND gates.
Multistep network reactions in biological systems were shaped
through millions of years of evolution.[1] In extant biological
processes, cascades involving divergent, convergent, coupled, or
sequential steps lead to diverse chemical transformations that are
complex yet synchronized.[2] These cascades play critical roles in
the living systems, from cellular metabolism, signal transduction
to feedback guided oscillatory reactions on regulatory functions
and so forth.[2a,3] Compartmentalized environments featuring
spatially confined multiple enzyme complexes within subcellular
organelles act as microreactors for simultaneous oxidative and
biosynthetic pathways to build essential biomolecules and
catabolize energy sources. The team play between enzymes,
where products of one biocatalyst act as substrates for others,
enrich the local reactant concentrations which lead to improved
proficiency of the complex cascade transformations.[3b,4-7]
Mimicking such systems can have implications in the design of
enzymatic fuel cells, disease diagnostics, biosensors, catalysis
and synthesis of pharmaceuticals.[8] Further, defining such
complex chemical networks can contribute to our understanding
of the emerging field of systems chemistry.[9]
Figure 1. Schematic representation of different types of cascade reactions on
the surface of amyloid nanotube. TEM (a) and AFM (b) of the Im-KLVFFAL (Im-
KL) nanotubes, respectively.
Towards this end, we argued that the paracrystalline surfaces of
short amyloid phases could behave as self-assembled organelles
that can foster complex cascade reactions. Cross β amyloid
phases accessed by short peptides are known for their
remarkable binding capabilities towards diverse guests, from
small molecules to large macromolecules.[10-12] Further, the
inherent catalytic abilities of the repetitive amyloid structures are
often argued as the earliest protein folds.[13-15] Herein, we have
utilized the binding and catalytic potential of the cross-β amyloid
to load sarcosine oxidase (SOX) and a prosthetic group hemin to
devise nanohybrids that promote two-step, three-step, and
We used the hydrophobic nucleating core (17LVFFA21) of wild type
Aβ (1-42) sequence recognized for protein deposits seen in
Alzheimer’s disease.[8c,11-12] The pentapeptide has been shown to
access diverse morphologies with the propensity to non-
covalently bind proteins as well as small molecules.[11c-e] The
termini modification of this core leads to Im-KLVFFAL-NH2 (Im-
KL, Figure 1) which assembles into homogeneous nanotubes
(diameter=50±10 nm, height=7.6±0.7 nm, Figure 1, S1).
Characteristic β-sheet signature with the antiparallel arrangement
was observed from CD and FTIR respectively (Figure S2-
3).[14,15a,b] Powder X-ray diffraction (PXRD) showed reflection at d-
spacing of 4.67 Å and 10.63 Å which corresponded to the H-
bonded β-strand and β-sheet laminate distances respectively
(Figure S4).[14a] To probe the surface exposure of imidazoles and
lysines, negatively charged gold nanoparticles (GNPs) were
added. Ordered arrays of GNPs on the nanotube surface were
[a]
[†]
Department of Chemical Sciences & Centre for Advanced
Functional Materials,, Indian Institute of Science Education and
Research (IISER) Kolkata, Mohanpur, West Bengal, 741246, India
E-mail: dasd@iiserkol.ac.in
A.C. and C.M. contributed equally.
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observed, suggesting the presence of solvent-exposed cationic
groups that help in colloidal stability (Figure S5).[14a]
separately used, SOX bound Im-KL and hemin bound Im-KL,
they did not show any noticeable activity (Figure 2e, S9). This
result suggested that the co-localization of the catalysts on the
amyloid surface helped in facilitating the cascade reaction via
increasing the local concentration of the substrates.
To exploit Im-KL nanotubes for templating a simple two-step
oxidase-peroxidase cascade, SOX, a peroxisomal enzyme in
mammals and sarcosine-inducible enzyme in soil bacteria, was
used.[16a] The flavoenzyme catalyzes oxidative demethylation of
sarcosine (SAR) to glycine, formaldehyde and simultaneous
formation of H2O2, which fuels the second reaction (Figure 2).[16a-
c]
Rather than using an additional enzyme, we explored the
possibility of hemin bound amyloid folds to act as
a
peroxidase.[11e] Hemin, present in extant peroxidases and
metalloenzymes, has low intrinsic peroxidase activity in the free
state.[11e] Hemin bound nanotubes were characterized thoroughly
using UV Vis spectroscopy. Free hemin (pH 8 buffer) showed
Soret peak at 388 nm and a broad shoulder peak at 366 nm
indicating the presence of dimeric (μ-oxo bihemin) and some
monomeric hemin hydroxide (haematin). A low-intensity Q band
at around 620 nm also suggested the presence of μ-oxo bihemin
in free state.[17] In contrast, hemin bound to nanotubes showed
Soret peak at 412 nm and charge transfer transitions at ca. 626
and 530 nm, suggesting imidazole-hemin coordination (Figure
S6).[17] Notably, the peak intensity of bound hemin at 366 nm was
very weak in comparison to free state. This suggested reduction
of dimerization and formation of monomeric haematin on
nanotube surface.[17d]
To calculate loading, Im-KL nanotube was exposed to different
amounts of hemin, incubated for 30 min followed by ammonium
hydroxide washes to remove non-specifically bound hemin
(SI).[18a] Loading was calculated to be 79.8±5 µg-mg-1 with the
help of standard plot (Figure S7-8). Notably, at lower
concentrations (up to 5 µM), all hemin was found to be loaded on
the surface. To generate Im-KL-hemin-SOX nanohybrid, hemin
(5 µM) loaded nanotube was exposed to SOX (5 μM). From
Bradford Assay, entire enzyme concentration was observed to be
bound to the nanotubes (SI). AFM showed distinct globular
structures on the nanotube surface with line analysis
demonstrating increase of height from ca. 7.6±0.7 nm to 11.1±1.8
nm (Figure 2b). We further used CLSM to analyze the co-
localization of hemin and SOX on the nanotube surface through
fluorescein labelled hemin and rhodamine B isothiocyanate
(RITC) tagged SOX.[18b] At excitation of λ=490 nm, CLSM showed
fluorescent fibrillar networks (Figure 2c). Notably, when excited at
556 nm, distinct nanotubular networks were clearly visualized that
corresponded to the RITC labeled SOX (Figure 2c). Notably, the
software-merged image indicated the overlapping of fluorescent
fibrillar morphologies, thus underpinning the co-localization of the
two guests.
Figure 2. (a) Schematic representation of two-step cascade reaction. b) AFM
images of SOX bound to Im-KL (left), line scans (center) and colour-coded AFM
images for heights (right). c) CLSM images of Im-KL bound to RITC-labelled
SOX (left), FITC-labeled hemin (center), and merged image (right). d) UV
absorbance spectra (λmax=470 nm) and e) kinetic spectra of the two-step
cascade reaction monitored at λmax=470 nm.
For the two-step cascade reaction, the activity was monitored by
adding the substrate SAR along with guaiacol (GU) as the well-
known chromogenic substrate.[16d] We expected that the bound
SOX will aerobically oxidize SAR to generate H2O2 which will be
subsequently utilized by hemin to catalyze the oxidation of GU to
a brown product (Figure 2a). The kinetics of tetraguaiacol product
formation was monitored by UV-Vis spectroscopy (λmax=470 nm,
Figure 2d,e). The activity of the cascade by Im-KL-hemin-SOX
was found to be 6.4±0.8 μM-min-1 with 25 mM of SAR (Figure 2e,
S9). Interestingly, cascade activity in the presence of nanotubes
was 8.5-fold higher compared to the controls of free hemin-SOX-
histidine diffusional mixture at the same concentration. When
At this point, we sought to explore the intrinsic hydrolase-like
activity of the imidazole exposed amyloid surfaces that could
facilitate the three-step biocatalytic cascade reaction.[14] For this
purpose, we used acetylated sarcosine (Ac-SAR) which can be
hydrolyzed to SAR by the imidazole exposed amyloid nanotubes
(Figure 3a). Subsequently, in the second step, SOX bound to
nanotubes will consume SAR to generate H2O2 which would act
as substrate for GU oxidation catalyzed by bound hemin (Figure
3a). Interestingly, the three-step cascade product was indeed
formed when Ac-SAR was added to Im-KL-hemin-SOX (2.03±0.6
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μM-min-1, Figure 3b, S10). To the best of our knowledge, this is
the first example of a three-step cascade reaction where only one
comparatively smaller enzyme is used instead of three large
enzymes. The activity of Im-KL-hemin-SOX was 26-fold higher
compared to the free diffusional mixture of SOX, hemin and
histidine at equal concentrations (0.08±0.04 μM-min-1, Figure 3b,
S10). To probe the hydrolytic role of imidazole moiety, we
replaced it with an acetyl group (Ac-KLVFFAL, Ac-KL). Ac-KL
assembled to form indistinguishable nanotubular structures as
seen for Im-KL (diameter 32±3 nm, Figure S11).[12b,15b] Notably,
activity for Ac-KL decreased significantly (0.14±0.1 μM-min-1,
Figure 3c, S12) and thus highlighted the vital role of imidazoles of
Im-KL. Further, we added free histidine to Ac-KL which indeed
augmented the activity (0.55± 0.8 μM-min-1) but still was 3.6-fold
lower compared to Im-KL (Figure 3c, S12). These results
corroborated the crucial role of the arrays of imidazoles installed
on the Im-KL surface for the hydrolysis step of the multistep
cascade reaction.
activity by SOX-hemin bound Im-KL, Ac-KL and Ac-KL with histidine, d) Three-
input Boolean AND logic gate, by SOX, hemin, and Im-KL as the chemical
inputs.
The use of molecule-based logic gates has emerged as an
exciting tool for many potential applications.[19] Biological
processes take place in the aqueous milieu and are connected by
various electrochemical and supramolecular interactions. Hence,
logic gates in wet platform utilizing inputs such as metabolites, pH,
ions and so for the while providing useful outputs (colour,
fluorescence etc.) can be useful in processing the
chemical/biochemical information.[19] To highlight the significance
of every component of the nanohybrid for the multistep cascade,
AND gate was constructed with peptide, SOX, and hemin as the
inputs and absorbance at 470 nm as output which could also be
seen with the naked eye (Figure 3d). When any one of the
components of Im-KL-hemin-SOX was used as the input
(1,0,0/0,1,0/0,0,1), the reaction did not cascade to the output (0).
The combination of two components (1,1,0/1,0,1/0,1,1) also
resulted in no output (0). Only the incorporation of all three inputs
(1,1,1) resulted in the output (1, Figure 3d).
We sought to construct a complex convergent cascade system
which is seen in protein signaling and nervous systems.[2] We
coupled two critical inputs of the cascade, SAR and GU to form
an ester (SAR-GU) with the expectation that Im-KL nanotubes will
hydrolytically release the components (Figure 4a). SAR-GU will
thus provide SAR, which will be degraded to H2O2 that will
subsequently converge with the other fragment (GU). Remarkably,
the cascade product was indeed formed by Im-KL-hemin-SOX as
confirmed from the colour change of the medium within 30 s of
the reaction. Figure 4b shows the time course generation of the
product (red curve) whereas controls show very low rates. The
cascade activities of Im-KL-hemin-SOX (13.4±2 μM-min-1) were
30-fold higher than those of free SOX, hemin and histidine
mixtures (0.44±0.2 μM min-1, Figure S13). This significant
improvement of activity could be attributed to the substrate
channelling effect where the generated H2O2 was rapidly
consumed by the proximally located hemin in presence of in-situ
generated GU. As control, freshly disassembled Im-KL in
presence of unbound hemin and SOX was used (Figure S14, SI).
The activity was found to be very low (0.8±0.3 μM-min-1) which
underpinned the importance of co-localization of hemin and SOX
on the surface of the nanotube. Kinetic study further suggested
that the hydrolysis step was slower compared to the terminal
oxidation step (Figure S15-17). Moreover, to understand this
aspect, we divided Im-KL-hemin-SOX into two parts. Half of the
nanotubes were incubated with SOX and the other half with hemin
in separate microcentrifuge tubes so that each batch of nanotubes
will feature only one particular guest. The activity of this mixture
was found to be 45% of the native activity (Figure S18).
We argued that the complexity of a chemically system is not only
limited to a single Boolean logic operation (AND or OR) but can
Figure 3. Schematic representation of three-step cascade, b) Time-dependent
kinetics of the three-step cascade reaction, c) bar diagram of the cascade
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Figure 4. a) Schematic representation of convergent cascade, b) Time-dependent kinetics of different systems, c) Logic network representation of the cascade
reaction with different Chemical Input Signals and inset showing the image of the chromogenic output.
be extended to the construction of complex combinatorial multi-
gate logic networks. This usually required compatible inputs that
can cascade the information throughout the networks to provide
the output. A three-concatenated AND gate was constructed
utilizing multiple biologically important stimuli as inputs (Figure 4c).
The operation made by Im-KL-hemin-SOX on the inputs i.e. SAR-
GU and H2O, resulted in the output of SAR and GU, thus
successfully constructing an AND gate. Subsequently, one more
AND gate was constructed with the help of inputs oxygen
(dissolved in water), SAR (output of first AND gate). Interestingly,
output of the first AND gate i.e. GU and the output of second AND
gate i.e. H2O2 converged as the inputs for a third AND gate
resulting in the final output (color) via concatenation of AND gates
(Figure 4c). Unprecedentedly, three sequential AND gates were
integrated within a simple chemical system where output and
input from different steps converge to make a closed network.
Such complexity is seen in convergent signalling pathways of
extant biology.
In summary, the present study demonstrates the generation of a
single enzyme based nanohybrid that can facilitate diverse
cascade reactions, from two-step, multistep to complex
convergent cascades. The nanotubular hybrids were created by
loading enzyme SOX and molecular hemin on the paracrystalline
imidazole rich surface of short peptide based amyloid assemblies.
Further, complex digital design of combinatorial chemoelectronic
logic networks has been proposed with the help of suitable
chemical inputs that foreshadowed the convergent cascade. The
general strategy and design flexibility of such amyloid
nanohybrids make the developed systems adaptable for
accessing intelligent soft material.
Experimental Section
Experimental details in supporting information.
Acknowledgements
For financial support, DD, AC and CM are thankful to SERB
(EMR/2017/005126), DST, GOI., CSIR and Nano Mission
(SR/NM/NS-1082/2015) respectively.
Keywords: Amyloid • Peptide Self-assembly • Enzyme Mimics •
complex cascade • Logic gates
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10.1002/anie.202011454
Angewandte Chemie International Edition
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Complex Cascade-
effect: Amyloid based
minimalistic systems
have been shown to
demonstrate diverse
Ayan Chatterjee,†
Chiranjit Mahato†
and Dibyendu Das*
Page No. – Page
No.
cascade
networks,
reaction
starting
Complex Cascade
Reaction
from simple two-step,
multistep to complex
convergent cascades.
Networks
via
Cross β Amyloid
Nanotubes
Further,
complex
chemoelectronic
computations
were
done with the help of
multi
concatenated
gates.
input,
AND
This article is protected by copyright. All rights reserved.