Designed Negative Feedback from Transiently Formed Catalytic Nanostructures

Article abstract of DOI:10.1002/anie.201910280

Highly dynamic and complex systems of microtubules undergo a substrate-induced change of conformation that leads to polymerization. Owing to the augmented catalytic potential at the polymerized state, rapid hydrolysis of the substrate is observed, leading to catastrophe, thus realizing the out-of-equilibrium state. A simple synthetic mimic of these dynamic natural systems is presented, where similar substrate induced conformational change is observed and a transient helical morphology is accessed. Further, augmented catalytic potential of these helical nanostructures leads to rapid hydrolysis of the substrate providing negative feedback on the stability of the nanostructures and realization of an out-of-equilibrium state. This simple system, made from amino acid functionalized lipids, demonstrates a substrate-induced self-assembled state, where the fuel-to-waste conversion leads to the temporal presence of helical nanostructures.

Full text of DOI:10.1002/anie.201910280

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International Edition: DOI: 10.1002/anie.201910280
German Edition: DOI: 10.1002/ange.201910280
Systems Chemistry
Designed Negative Feedback from Transiently Formed Catalytic
Nanostructures
Syed Pavel Afrose, Subhajit Bal, Ayan Chatterjee, Krishnendu Das, and Dibyendu Das*
Abstract: Highly dynamic and complex systems of micro-
tubules undergo a substrate-induced change of conformation
that leads to polymerization. Owing to the augmented catalytic
potential at the polymerized state, rapid hydrolysis of the
substrate is observed, leading to catastrophe, thus realizing the
out-of-equilibrium state. A simple synthetic mimic of these
dynamic natural systems is presented, where similar substrate
induced conformational change is observed and a transient
helical morphology is accessed. Further, augmented catalytic
potential of these helical nanostructures leads to rapid
hydrolysis of the substrate providing negative feedback on
the stability of the nanostructures and realization of an out-of-
equilibrium state. This simple system, made from amino acid
functionalized lipids, demonstrates a substrate-induced self-
assembled state, where the fuel-to-waste conversion leads to the
temporal presence of helical nanostructures.
energy consumption pathways.[9] To the best of our knowl-
edge, none of the reported systems mimic the two critical
events of microtubule assembly and disassembly, namely
1) non-covalent binding of GTP to ab-tubulin building block
leads to change of conformation and the onset of polymer-
ization under thermodynamic control and 2) accelerated
cleavage of GTP owing to augmented catalysis from con-
formationally discrete polymerized state result in switch of
conformation and disassembly (Figure 1a).[30–32] The tubulin
building blocks undergo phase transition from a tilted to
I
n living systems, complex processes such as self-assembly of
cytoskeleton proteins involve substrate induced realization of
assembled states that can dissipate energy.[1–9] Specifically in
microtubules, a dynamic filament-like morphology is accessed
by self-assembly of tubulin protein building blocks, after
binding with substrate guanosine triphosphate (GTP), which
are subsequently hydrolyzed. Through remarkable spatio-
temporal control, these transient nanostructures carry out
a myriad of advanced functions, from providing support
girders to cells to dynamic motility and so forth.[5,6] Efforts
have been made to mimic these intelligent out-of-equilibrium
natural systems by simple chemical systems.[7–10] Mimicking
and recognizing these complex systems can help in the
realization of exciting new smart materials and molecular
machines.[4,7,11,12] Initial reports on transient self-assembled
systems have used chemical fuels that are kinetically stable
molecules or light as the energy source to access assembled
state.[7,13–26] However, for the energy dissipation step, most of
these reported systems relied on the external roles of
catalysts, such as enzymes or environmental switches.[14–18,20–27]
In contrast, the natural dynamic filaments rely on the
augmented catalytic prowess of the self-assembled state to
dissipate energy and thus features kinetic asymmetry in
Figure 1. a) The formation of microtubules: Guanosine triphosphate
(GTP) binds to tubulin monomers, induces change of conformation
from tilted to straight, and drives self-assembly and polymerization.
Augmented catalytic activity of the assembled polymers of straight
conformation (marked with an asterisk) results in hydrolysis and
release of GDP. b) The present work, showing metastable helical
nanostructures: Substrate F-NP induces the formation of new con-
formation and drives the assembly of helical nanostructures. Aug-
mented catalytic rates from helical assembled state (marked with an
asterisk) leads to release of NP. Chemical structures of molecules
involved are shown.
[*] S. P. Afrose, S. Bal, A. Chatterjee, K. Das, D. Das
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
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.201910280.
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straight conformation in presence of GTP, subsequently
hydrolyzing it and finally relapsing to the tilted conformation
of the building blocks (Figure 1a). The out-of-equilibrium
state is accessed owing to this emergence of augmented
enzymatic GTPase activity at this conformationally distinct
assembled state (Figure 1a).[28,29] Substrate-induced access of
active conformation is also widely exploited in extant biology
for accelerating catalysis.[33–36]
In the present work, we show the out-of-equilibrium
generation of a conformationally distinct assembled state
induced by substrate, accelerated catalysis, and relapse to the
initial state (Figure 1b). Simple amino acid based amphiphiles
have been shown to access out-of-equilibrium helical mor-
phology in presence of a kinetically stable ester. We show
evidence of the time-dependent generation of a new phase,
rate acceleration negative feedback and disassembly.
We used n-stearoyl l-histidine[37] (H, Figure 1b), which
does not form a self-supporting supramolecular hydrogel until
a concentration of 38 mm in DMSO/water (20%, v/v). Owing
to the presence of histidine in the structure, H was expected to
be a catalyst, albeit with modest abilities.[19] To help H access
a metastable assembled state with possible acceleration of
catalysis, we added p-nitrophenyl ester of n-stearoyl l-phenyl
alanine (F-NP, Figure 1b). The reason for choosing F-NP as
the substrate was due to its lipid tail and phenyl ring, which
will render it prone to coassembly, and the activated
chromogenic ester can be utilized to monitor the rate of
hydrolysis. Notably, at concentration up to 50 mm, F-NP did
not yield any gel with DMSO/water (20%, v/v). Interestingly,
when F-NP (DMSO stock) was added to H (in DMSO, at 1:1
ratio, 30 mm each; see the Supporting Information for
details), we observed gradual thickening of the mixture.
This process of self-assembly will be referred as SYS1 in
the rest of the manuscript. The SYS1 solution eventually
formed a self-supporting weak gel after about 2 h (Figure 2a).
Intriguingly, these gels showed weakening over time with
a gel-to-sol transition, and on some occasions showed phase
separation (see the Supporting Information for details).
Simultaneous intensification of yellow color was also
observed over time, indicating gradual hydrolysis of the
substrate F-NP by the catalyst H. To investigate this
observation in more detail, rheology was performed on
a 1:1 mixture of the component catalyst H and substrate F-
NP (30 mm each, SYS1 in Figure 2c, and the Supporting
Information, Figures S1, S2). A time-dependent rheology
study revealed gradual increase of storage modulus for the
two-component system. This increase of storage modulus
corroborated with the observation of gel formation in 2 h. The
storage modulus after registering a highest value at about 2 h
showed a gradual decrease with time (Figure 2c).
Figure 2. a) SYS1 process of assembly, which leads to the generation
of metastable helical nanostructuresm as suggested from time-
resolved electron-microscopy images. Vial images show time-depen-
dent change of gel and sol. b) SYS2 process of assembly where F-NP
was added after 12 h of assembly of H and corresponding vial images
at different time intervals. c) Rheology showing variation of G’ and G’’
with time for SYS1 and SYS2; error bars represent the data for three
individual experiments. d) CD spectra of H, F-NP, SYS1 and the
analytical addition of the corresponding experimental spectra of H and
F-NP. e) Disappearance of peak at 275 nm for SYS1 with time along
with the spectra of a system containing mixture of H and the products
F and NP.
investigate this, the samples were probed with circular
dichroism (CD) spectroscopy. Importantly, CD revealed the
emergence of a band at 275 nm, which was missing for either
of the individual components H and F-NP, respectively
(Figure 2d). Interestingly, the CD spectrum of the SYS1 was
completely different from the analytical addition generated
from the simple sum of the CD traces of H and F-NP
(Figure 2d). This suggested co-assembly of the components H
and F-NP.[38,39] Furthermore, CD was recorded for the
concentration of the components by varying from 100% H
(60 mm) to gradually up to 100% F-NP (60 mm) at time t
ꢀ 0 h (Supporting Information, Figure S4a). We also plotted
Notably, none of the individual component H or F-NP at
60 mm individual concentrations had storage modulus higher
than what was observed for the co-assembled samples
(Supporting Information, Figure S3). This temporal variation
of the mechanical properties indicated the generation of
a substrate-induced metastable state which was transient in
nature. Also, the gelation studies and the rheology experi-
ments suggested the SYS1 mixture of amphiphile H and F-NP
was temporally accessing a high-order assembled state. To
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the analytical addition of the individual experimental spectra
no defined structures initially at t ꢀ 0 h (Figure 3d; Support-
of H and F-NP (Supporting Information, Figure S4b) and
compared the intensities at their individual lmax (Supporting
Information, Figure S4c). The comparison showed gradual
increase of intensity up to 50:50 and thus underpinned the
coassembly of H and F-NP. Notably, the CD band at 275 nm
showed a gradual weakening in intensity with time (Fig-
ure 2e; Supporting Information, Figures S5, S6, S25). CD
spectra of SYS1 after 10 h was similar to the spectra of the
mixture of H, F, and NP (Figure 2e).
Since CD suggested generation of a new transient
conformation for SYS1, we used transmission electron
microscopy (TEM) to investigate the samples thoroughly.
Initially, the individual components H and F-NP were
investigated with TEM. H showed mostly short fibril like
morphology of diameter 39 Æ 9 nm (Supporting Information,
Figure S7). F-NP when imaged under TEM did not have any
defined structures (Supporting Information, Figure S8).
Remarkably, time-dependent TEM (Figure 3a–c) carried
out with SYS1 (1:1 mixture of H and F-NP) revealed gradual
emergence of well-defined helical ribbons after about 2 h. The
width of the helices ranged from 40–70 nm, with lengths
ranging from 1.5 to 3 mm (Figure 3b; Supporting Information,
Figure S9). The pitch ranged around 230 Æ 30 nm (Supporting
Information, Figure S9). A histogram of population from
multiple TEM images for four separate experiments revealed
ing Information, Figure S10). With time, a surge in population
of helical nanostructures was observed, with the 4 h micro-
graph showing 90% of the population featuring helical
morphology (Supporting Information, Figure S10). To further
confirm the structures, thorough time resolved cryo-electron
microscopy (Cryo-EM) for four separate experiments was
carried out. Cryo-EM also showed temporal generation of
helical nanostructures. Histograms and representative images
are provided in Supporting Information (Supporting Infor-
mation, Figures S11, S12). SEM also supported the presence
of helices (Supporting Information, Figure S13). After 6 h,
the population of helices started to decline with some images
showing unwinding of helices (Supporting Information,
Figures S10, S11, S14). At 10 h, population of fibrils increased
with almost no presence of helical morphology (Figure 3d;
Supporting Information, Figures S10, S11). To the best of our
knowledge, this substrate induced generation of a new con-
formational state which provides negative feedback to its own
stability is unprecedented in synthetic systems.
To gain further insights of the generation of the transient
nanostructures, we employed fluorescence spectroscopy. We
used a hydrophobic fluorophore Nile Red as the probe for the
time-dependent monitoring of these transient helical mor-
phologies. Nile Red is known for its sensitive reporting of the
microenvironment for the assembly of lipid functionalized
amphiphiles.[40] Expectedly, the fluorescence showed tempo-
ral increase and decrease of intensity reflecting the generation
of a transient hydrophobic phase (Figure 4a; Supporting
Information, Figure S15). This temporal change of fluores-
cence intensity matched with the transient rise and fall of
population of helices, as observed from TEM (Figure 4a,
represented by blue). Interestingly, this intensity versus time
plot also disclosed a rapid growth after an initial lag of about
10 min suggesting the nucleation phase. From 20 to 40 min,
there was sharp increase of intensity, which stayed until about
5 h before showing gradual decline (Figure 4a). We predicted
that if this nucleation phase is avoided, the self-assembled
state of helices will not be accessed. Hence, we delayed the
association of the substrate F-NP. Until now SYS1 involved
the mixing of catalyst H and substrate F-NP in DMSO before
addition of water (Figure 2a). For SYS2 (Figure 2b), we
incubated H for 12 h, and then added F-NP (Figure 2b,
referred to as SYS2).
Notably, for SYS2 no gel formation was observed when
the aged H assembly was mixed with F-NP (Figure 2b).
Furthermore, emergence of no new peak could be observed in
CD and the resultant trace was similar to a simple sum of the
two individual spectra of H and F-NP (Supporting Informa-
tion, Figure S16). Rheological experiments showed no tran-
sient increase of storage modulus and thus underpinned the
incapability of SYS2 to access a temporally enhanced
viscoelastic property that can result in gelation (Figure 2c;
Supporting Information, Figure S1). We were curious to
investigate the morphology of the assembled structures.
Time-resolved TEM imaging carried out with the SYS2
samples showed images dominated with fibrillar structures
and other undefined morphologies (Figure 3e; Supporting
Information, Figure S17). This suggested that coassembly in
Figure 3. Representative TEM images of SYS1 at a) 0 h, b) 4 h, and
c) 10 h. Population pyramid of time-dependent change of fibers versus
helices for d) SYS1 and e) SYS2.
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rapid phase of SYS1. The lower activity in SYS2 is
surprising from the context of supramolecular catalysis
where pre-assembled structures usually show augmented
activity owing to the presence of a rich surface of solvent-
exposed catalytic residues.[41–46] Hence, the activation in
SYS1 underpinned the role of a new conformational state,
augmentation of catalytic potential, and subsequent neg-
ative feedback on the stability of the nanostructures. From
HPLC, the conversions were found to be 4.5 Æ 0.7 mm
after 360 min for SYS1, suggesting about 15% hydrolysis
of F-NP (Supporting Information, Figures S20, S21).
For a control, we also used a smaller substrate which
does not coassemble with H, and hence will be incapable of
accessing helical morphologies (Figure 4d; Supporting
Information, Figure S22). Indeed, when 4-nitrophenyl
ester of acetic acid (P-NPA) was used instead of the
hydrophobic ester F-NP, SYS2P-NPA showed higher activity
(Vi = 22.8 Æ 1 mm sÀ1) rather than SYS1P-NPA (Vi = 11.5 Æ
0.3 mm sÀ1
;
Figure 4e; Supporting Information, Fig-
ure S23). This result further supported the remarkable
catalytic role of the out of equilibrium helical morpholo-
gies accessed for the coassembled H-F-NP system (SYS1).
Finally, pH versus rate profile study was carried out to
investigate whether cooperative catalysis from neighbor-
ing histidines are responsible for higher activity in
SYS1.[19,36] Indeed, highest activity at pH 6 suggested the
cooperative effects of histidines are playing a role for the
high activity at the helical assembled state (Supporting
Information, Figure S24).
In conclusion, we have developed a simple synthetic
system that undergoes substrate induced assembly and
accesses a helical conformation state. This emergent
morphology shows augmented catalytic potential to sub-
sequently cleave the same substrate and undergoes
spontaneous disassembly. Notably, the assembly exhibited
multiphasic rate of hydrolysis of the substrate where an
initial lag phase to access the catalytic conformation was
followed by an accelerated hydrolytic phase for the
conversion of fuel to waste. This journey of self-assembly in
the simple system is remarkably analogous to the aggregation
process of complex systems of microtubules where similar
substrate triggered change of conformation and polymeri-
zation is seen. Further, in microtubules, accelerated hydrol-
ysis in polymerization state with rapid release of phosphates is
also seen. Notably, in our simple system, augmented catalysis
from the assembled state provides a negative feedback for
assembly thus removing the need for external factors such as
enzymes. Also, the present system demonstrates a transient
self-assembled system, where the fuel-to-waste conversion
leads to the temporal formation of helical nanostructures.
Although the reported system is interesting with such unique
behavior, we are currently working towards alternative
molecular systems, which can display similar properties.
Figure 4. a) Time-dependent fluorescence for SYS1 and SYS2. Error bars
represent standard deviations of three independent measurements. The
intensity band represents broadly the percentage of helices. b) Time-course
kinetics of hydrolysis of F-NP for SYS1 and SYS2. c) Bar diagram showing
the lag phase and rapid phase of initial rates for SYS1. Error bars represent
standard deviations of three independent measurements. d) SYS1 and
SYS2 for P-NPA. e) Bar diagram showing relative normalized rates of
hydrolysis for SYS1 and SYS2 for F-NP (left) and P-NPA (right).
SYS1 indeed leads to the generation of the out-of-equilibrium
helical morphologies. Fluorescence spectroscopy also did not
register any temporal increase of intensity for SYS2 (Fig-
ure 4a).
We expected that the temporal increase of fluorescence
intensity, transient generation of new CD peak, and time-
dependent rise and fall in population of the helices should be
reflected in the catalytic rates. Intriguingly, the absorbance
versus time plot showed a well-defined triphasic nature with
a clear initial lag phase to access the helical structures,
followed by accelerated rate of hydrolysis and finally
a saturation phase (Figure 4b). This rate of accelerated
catalytic phase (Vi = 5.9 Æ 0.5 mm sÀ1) was 3.7 fold higher
than the activity seen in the lag phase (Vi = 1.58 Æ 0.3 mm sÀ1,
Figure 4b,c; Supporting Information, Figure S18). The fact
that the rapid phase starts from as early as 20 min shows the
fuel-to-waste conversion leads to the realization of the
temporal self-assembled helical nanostructures. In contrast,
the SYS2 structures did not display such accelerated kinetics
for hydrolysis (Figure 4b; Supporting Information, Fig-
ure S19). Significantly, the rates for SYS2 (average rate Vi =
0.6 Æ 0.01 mm sÀ1) was an order of magnitude lower than the
Acknowledgements
D.D. is thankful to SERB (EMR/2017/005126), DST, GOI.
S.P. A., A.C., and K.D. acknowledge UGC, CSIR and Nano
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Keywords: catalysis ·dissipative self-assembly ·gels ·
nanostructures ·systems chemistry
How to cite: Angew. Chem. Int. Ed. 2019, 58, 15783–15787
Angew. Chem. 2019, 131, 15930–15934
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Accepted manuscript online: September 2, 2019
Version of record online: September 20, 2019
Angew. Chem. Int. Ed. 2019, 58, 15783 –15787
ꢀ 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 15787