A Light-Operated Molecular Cable Car for Gated Ion Transport

Article abstract of DOI:10.1002/anie.202102838

Inspired by the nontrivial and controlled movements of molecular machines, we report an azobenzene-based molecular shuttle PR2, which can perform light-gated ion transport across lipid membranes. The amphiphilicity and membrane-spanning molecular length enable PR2 to insert into the bilayer membrane and efficiently transport K⁺ (EC₅₀=4.1 μm) through the thermally driven stochastic shuttle motion of the crown ether ring along the axle. The significant difference in shuttling rate between trans-PR2 and cis-PR2 induced by molecular isomerization enables a light-gated ion transport, i.e., ON/OFF in situ regulation of transport activity and single-channel current. This work represents an example of using a photoswitchable molecular machine to realize gated ion transport, which demonstrates the value of molecular machines functioning in biomembranes.

Full text of DOI:10.1002/anie.202102838

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How to cite:
International Edition: doi.org/10.1002/anie.202102838
German Edition: doi.org/10.1002/ange.202102838
Molecular Machine Very Important Paper
A Light-Operated Molecular Cable Car for Gated Ion Transport
Chenxi Wang+, Shunkang Wang+, Huiting Yang, Yanxin Xiang, Xuebin Wang, Chunyan Bao,*
Linyong Zhu, He Tian, and Da-Hui Qu*
Dedicated to Professor Vincenzo Balzani on the occasion of his 85th birthday
Abstract: Inspired by the nontrivial and controlled movements
of molecular machines, we report an azobenzene-based
molecular shuttle PR2, which can perform light-gated ion
transport across lipid membranes. The amphiphilicity and
membrane-spanning molecular length enable PR2 to insert
into the bilayer membrane and efficiently transport K+ (EC50 =
4.1 mm) through the thermally driven stochastic shuttle motion
of the crown ether ring along the axle. The significant
difference in shuttling rate between trans-PR2 and cis-PR2
induced by molecular isomerization enables a light-gated ion
transport, i.e., ON/OFF in situ regulation of transport activity
and single-channel current. This work represents an example of
using a photoswitchable molecular machine to realize gated
ion transport, which demonstrates the value of molecular
machines functioning in biomembranes.
molecular knots.[10] Recently, our group also reported that
an artificial molecular shuttle acted like a cable car in
a bilayer membrane for selective ion transport, i.e., passively
transported K+ ions based on the stochastic back-and-forth
shuttling of a wheel along a thread.[11]
In addition to the ion selectivity and efficiency, the gated
ion transport also plays an important role in nature. Chan-
nelrhodopsins (ChRs) are a class of representative light-gated
cation channels.[12] They perform gated ion transport through
photoinduced conformational transformation and play an
important physiological role in nerve signal transduction.
Chemical photoswitches are molecules that can rapidly and
reversibly transform their conformations under light stimula-
tion. Inspired by the working mechanism of ChRs, chemical
photoswitches have been incorporated with protein channels
to realize gated ion transport.[13] However, due to the lack of
a synthetic architecture that can quickly respond to light in
lipid bilayers, synthetic transporters showing light-gated ion
transport are extremely rare.[14] Early designed photorespon-
sive surfactants are simply confined to changing the mem-
brane permeability by conformational transformation.[15] To
overcome this dilemma, it is necessary to design and
synthesize novel light-gated ion transporters.
I
on transport across the lipid bilayer is a key physiological
process of cells in regulating the pH value, maintaining
osmotic balance and transmitting cellular signals, which is
essential for the delicate operation of life.[1] Designing
artificial molecules to simulate this process can improve the
understanding of the working principle of natural ion trans-
porters,[2] and have great potential applications in life science
and materials science.[3]
It is well known that rotaxane-type systems can control
the shuttle process by photoinduced conformational trans-
formation of the photoswitch moieties.[16–19] If this light-
controlled shuttling can be incorporated into the rotaxane
transporter operated by our reported shuttle mechanism,[11a] it
will be possible to realize light-gated ion transport across lipid
membranes. As illustrated in Scheme 1, an azobenzene-based
molecular shuttle (PR2, Scheme 1a) was designed, which
includes an azobenzene-modified amphiphilic thread (PT2)
with two secondary ammonium ions as the terminal stations
for the shuttle and a wheel (RCE) consisting of a K+ selective
receptor, i.e., a benzo[18]crown-6 (B18C6) ring. The space
length between the two ammonium stations of PT2 is
approximately 3.43 nm (calculated according to the Corey-
Pauling-Koltun (CPK) model, Figure S1), which is compara-
ble to the hydrophobic thickness of a typical phospholipid
bilayer and enables the stable membrane-spanning arrange-
ment of the rotaxane.[20] We envision that when the azoben-
zene moiety is in the trans-form, the ring can freely shuttle
between the two secondary ammonium stations in the
membrane, which results in efficient ion transport (Sche-
me 1b). After irradiation with 365 nm light, the photoisome-
rization of the azobenzene moiety from the trans- to the cis-
form slows down or even prevents ring shuttling, which causes
the light-gated behavior for ion transport. Therefore, the
To simulate the high selectivity and efficiency of ion
transport by natural ion transporters, great efforts have been
made to develop artificial carriers or channels.[4] Some of
them focus on optimizing the structures of natural trans-
porters,[5] while others are committed to creating new
synthetic ion transporters such as tubular hosts,[6] helical
foldamers,[7] heteropolymers,[8] rigid-rod oligomers[9] and
[*] C. Wang,[+] S. Wang,[+] H. Yang, Y. Xiang, X. Wang, Prof. C. Bao,
Prof. L. Zhu, Prof. H. Tian, Prof. D.-H. Qu
Key Laboratory for Advanced Materials and Joint International
Research Laboratory of Precision Chemistry and Molecular Engi-
neering
Feringa Nobel Prize Scientist Joint Research Center
Frontiers Science Center for Materiobiology and Dynamic Chemistry
Institute of Fine Chemicals, School of Chemistry and Molecular
Engineering
East China University of Science and Technology
Shanghai 200237 (China)
E-mail: baochunyan@ecust.edu.cn
dahui_qu@ecust.edu.cn
[+] These authors contributed equally to this work.
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.202102838.
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Scheme 1. a) Molecular structure of molecular shuttle PR2 and b) pro-
posed mechanism for light-gated ion transport across lipid bilayers.
integration of a light-responsive molecular machine with
biological/biomimetic membranes will operate ion transport
in a controllable and reproducible manner.
PR2 was prepared by a typical “threading followed by
stopping” strategy (Schemes S1–S4). The interlocked struc-
ture can be verified by comparing the partial 1H NMR spectra
in CD3CN with thread PT2 and ring RCE. As shown in
Figure 1a, the appearance of complexed and noncomplexed
thread protons, i.e., Hc, Hd, and He, indicates that the ring
stays at one of the ammonium stations on the NMR time
scale. It also shows that there is the cis-isomer of PR2 (cis-
PR2) in CD3CN even without irradiation, and the trans-
isomer can be totally converted into cis-isomer upon 365 nm
UV irradiation. The photoconversion is further confirmed by
the evolution of absorption, which shows reversible switches
between trans- and cis-isomers (Figure 1b, Figure S2). To
investigate the isomerization effect on the shuttling rate,
NMR exchange spectroscopy (2D-EXSY, Figure S3, S4 and
Table S1) was performed, where CDCl3 was used as the
solvent because its hydrophobic environment is closer to the
phospholipid bilayer. After data processing, the shuttling rate
k of trans-PR2 is 0.214 Hz as calculated by the exchange
rates; however, no obvious exchange signal was detected
when PR2 was transferred into the cis-form upon 365 nm
irradiation. The reversible isomerization and controllable
shuttle motion of PR2 provide the premise for gated ion
transport across lipid bilayers.
To verify whether PR2 can insert into lipid bilayers to
perform ion transport, as in our previous molecular cable car,
dynamic light scattering (DLS) analysis was first performed.
Unlike the surfactant Triton X-100, which decomposes large
unilamellar lipid vesicles (LUVs), the addition of PR2 only
slightly broadens the particle size distribution and does not
break the membrane integrity (Figure S5). Differential scan-
ning calorimetry (DSC) was used to evaluate the ability of
compounds to incorporate liposomes, since it can monitor the
domain information of the lipid membrane. The results show
that the addition of PR2 obviously alters the endothermal
phase behavior of the membrane in the temperature range of
10–408C (Figure S6), which indicates the insertion of PR2 in
the lipid bilayers instead of only surface adsorption.[8,21] This
Figure 1. a) Partial 1H NMR spectra (600 MHz) of the ring RCE, thread
PT2 and rotaxane PR2 before and after 365 nm irradiation (2 min,
10 mWcmÀ2) in CD3CN at 1.0 ꢀ10À2 m. Subscript “t” and “c” indicate
the peaks assigned to trans- and cis-isomers, respectively. b) Reversible
photoswitching of PR2 (25.0 mm) in CH3CN monitored by UV/Vis
spectroscopy. The detection wavelength in the right panel is 360 nm.
conclusion can be further confirmed by the remaining
characteristic absorption peak of PR2 in LUVs after remov-
ing the extravehicular compounds by column purification
(Figure S7). A patch clamp technique on planar lipid bilayer
membranes (BLMs) was employed to record single-channel
current traces. The regular square-like signals with consid-
erably long opening times and the ohmic I–V profile confirm
that PR2 transports ions as fast as a stable channel or pore
across the bilayer membrane (Figure 2, Figure S8). The
conductance value was approximately 19 pS, which is close
to that of gramicidin A (23.2 pS), which indicates the efficient
transport of ions.[22]
An 8-hydroxy-1,3,6-pyrenetrisulfonate (HPTS) fluores-
cence-based LUVs assay was performed to explore the
transport activity of PR2.[11a] As illustrated in Figure 3a,
a pH gradient was applied to a solution of HPTS-encapsu-
lated LUVs (LUVsꢀHPTS) by addition of KOH (i.e., DpH =
0.8) in the extravesicular buffer; then the addition of trans-
porters induced the collapse of the pH gradient via a H+ efflux
or OHÀ influx, which led to the change in the ratio of
fluorescence intensity at 510 nm (I450/I405) of HPTS trapped
inside the vesicles. Trans-PR2 shows concentration-depen-
dent transport activity (Figure 3b) and reveals an EC50 (the
effective concentration required for 50% activity in 450 s)
value of 4.1 mm (12.4 mol% relative to lipid, Table S2), which
was significantly greater than that of subunits PT2 (Figure S9)
and comparable to our reported rotaxane transporter with
2
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(trifluoromethoxy)phenylhydrazone (FCCP), was added as
the cotransporter (Figure S13). The increased fractional
activity from 0.5 to 0.8 indicates that the transport of K+ is
faster than that of H+. To prove that ion transport of PR2 does
not originate from the disruption of the membrane, a HPTS
leakage experiment and a preincorporated LUVs assay were
performed (Figure S14,15). The low leakage and a comparable
transport activity (1 mol% to lipids) verify that the trans-
membrane activity originates from the insertion of PR2
rather than membrane destabilization. After UV light
irradiation, cis-PR2 exhibits much lower transmembrane
activity (Figure 3c,d) with an EC50 value of 20.1 mm (theoret-
ical value from Hill equation, 60.9 mol% relative to lipid).
The decrease in transport activity of cis-PR2 is consistent with
the suggested shuttling-based transport mechanism; i.e., the
limited shuttle motion of the cis-isomer reduces the transport
activity. This is notably different from membrane-active
molecules containing azobenzene, which exhibit an improved
ion transport ability after the cis-isomerization due to the
increased membrane disruption.[15]
Figure 2. a) Representative current recording and b) linear I–V plots of
PR2 (2.5 mm) at various holding potentials in a symmetrical 1 m KCl
solution; “open” means the opening of current signal; “closed” means
the current signal is zero; “level 1” means the signals from a single
channel; and “level 2” means the signals from two channels.
The in situ light regulation of PR2 in the membrane was
also performed by alternating irradiation between 365 nm
UV and 450 nm visible light. The UV/Vis absorption analysis
confirms the successful isomer transformation of PR2 in lipid
bilayers (Figure S7, Figure S16). The isomerization does not
result in the removal of molecules from lipids and the isomers
have good dark stability in the lipid membrane. Firstly, the
pH-gradient LUVsꢀHPTS assay was used to explore the in
situ optical switch of transport activity (Figure S17). To obtain
a longer observation period, activity tracking began with the
addition of cis-PR2 with low transport activity. As illustrated
in Figure 4a, the fractional activity shows light-gated ON/
OFF by alternating 450 nm and 365 nm illumination. This is
one of the few studies to observe in situ light-gated trans-
membrane activity using a liposome experiment.[24] Then,
single-channel conductance experiments on BLMs were
performed to exploit the light-gated behavior (Figure S18).
As illustrated in Figure 4b (Figure S19), reversible switching
between open and closed states was observed for the isomers
embedded in a lipid membrane. After the addition of cis-PR2,
no current signal was detected for a long time; however,
regular square-like signals appeared after 450 nm visible light
irradiation. If the patch was irradiated with 365 nm UV light
again, the channel current almost switched back to silent.
After more than 20 traces were counted, the opening
probability P0 of trans-PR2 was much higher than that of
cis-PR2. All these results support our hypothesis that
molecular machine PR2 can insert into the membrane to
transport ions like a cable car, and the conformational
transformation of azobenzene can reversibly regulate the
shuttling-rate to realize light-gated ion transport as
demanded.
Figure 3. a) Schematic illustration of the pH-sensitive LUVsꢀHPTS
assay. b,c) Ion transport activities of trans-PR2 (b) and cis-PR2 (c) at
0.1–16.6 mm. d) Comparison of the concentration–activity curves. The
red lines are the fitted curves from Hill equation (see Supporting
Information, section 9).
two stations, i.e., 6.7 mm.[11a] Further plotting the observed rate
constant kobs against the concentrations (Figure S10), the
linear correlation indicates the unimolecular active structure
of PR2 for ion transport. Considering the matching molecular
length of PR2 (3.43 nm hydrophobic spacer) with the thick-
ness of the insulator regime of lipid bilayers, we can conclude
that PR2 inserts and spans the entire bilayer to transport ions.
To explore the action of ionophore B18C6, both cation and
anion selectivity were explored and recorded by varying ions
outside the liposomes. PR2 exhibited obvious cation selec-
tivity and the transport activity follows the order of K+ >
Cs+ > Na+ ꢁ Rb+ > Li+ (Figure S11,12), which is inconsistent
with the energy penalty of ion dehydration,[23] indicating that
the ion recognition of B18C6 causes the K+ selectivity. It
suggests that either the K+/OHÀ symport or the K+/H+
antiport plays the key role for the fluorescence change of
HPTS. Then, a selective H+ transporter, carbonyl cyanide-4-
In summary, an azobenzene-based molecular shuttle PR2
was synthesized and used as a vehicle to develop a light-gated
ion transport function in lipid bilayer membranes. Due to the
geometrical transformations of the azobenzene moiety,
shuttle motions of PR2 can be controlled by light. Significant
differences in shuttling motion between trans-PR2 and cis-
PR2 result in light-gated K+ transport across lipid mem-
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Keywords: artificial ion transport · host–guest system ·
light-gating · molecular machine · rotaxanes
4
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Accepted manuscript online: April 11, 2021
Version of record online: && &&, &&&&
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Communications
Molecular Machine
Inspired by natural rhodopsin, an azo-
benzene-based molecular rotaxane was
designed to insert into lipid membranes
for the regulation of ion transport. Based
on the shuttle transport mechanism, the
significant difference in shuttling rate
between trans- and cis-isomer caused by
molecular isomerization facilitates light-
gated ion transport.
C. Wang, S. Wang, H. Yang, Y. Xiang,
X. Wang, C. Bao,* L. Zhu, H. Tian,
D.-H. Qu*
&&&& — &&&&
A Light-Operated Molecular Cable Car for
Gated Ion Transport
6
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These are not the final page numbers!