Molecular Swings as Highly Active Ion Transporters

Article abstract of DOI:10.1002/anie.201901833

Ions are transported across membrane mostly via carrier or channel mechanisms. Herein, a unique class of molecular-machine-inspired membrane transporters, termed molecular swings is reported that utilize a previously unexplored swing mechanism for promoting ion transport in a highly efficient manner. In particular, the molecular swing, which carries a 15-crown-5 unit as the ion-binding and transporting unit, exhibits extremely high ion-transport activities with EC₅₀ values of 46 nm (a channel:lipid molar ratio of 1:4800 or 0.021 mol % relative to lipid) and 110 nm for K⁺ and Na⁺ ions, respectively. Remarkably, such ion transport activities remain high in a cholesterol-rich environment, with EC₅₀ values of 130 (0.045 mol % relative to lipid/cholesterol) and 326 nm for K⁺ and Na⁺ ions, respectively.

Full text of DOI:10.1002/anie.201901833

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
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Accepted Article
Title: Molecular swings as extremely active ion transporters
Authors: Huaqiang Zeng, Changliang Ren, Feng Chen, Ruijuan Ye,
Yong Siang Ong, Hongfang Lu, Su Seong Lee, and Jackie
Ying
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201901833
Angew. Chem. 10.1002/ange.201901833
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10.1002/anie.201901833
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Molecular swing
DOI: 10.1002/anie.200((will be filled in by the editorial staff))
Molecular swings as extremely active ion transporters
Changliang Ren, Feng Chen, Ruijuan Ye, Yong Siang Ong, Hongfang Lu, Su Seong Lee, Jackie Yi-Ru Ying and
Huaqiang Zeng*
Abstract: Ions get transported across membrane mostly via
carrier or channel mechanisms. We report herein a unique class
of molecular machine-inspired membrane transporters, termed
molecular swings that utilize a previously unexplored swing
mechanism for promoting ion transport in a highly efficient
manner. In particular, the molecular swing, which carries a 15-
crown-5 unit as the ion-binding and transporting unit, exhibits
extremely high ion transport activities with EC50 values of 46 nM
(a channel:lipid molar ratio of 1:4800 or 0.021 mol% relative to
lipid) and 110 nM for K+ and Na+ ions, respectively. Remarkably,
such ion transport activities remain high in cholesterol-rich
environment, with EC50 values of 130 (0.045 mol% relative to
lipid/cholesterol) and 326 nM, respectively, for K+ and Na+ ions.
a)
MS-C5: n = 1
MS-C6: n = 2
Molecular transports across membrane are predominantly
mediated by either carriers[1] or channels.[2] Carriers do not span
the entire hydrophobic membrane region, often undergo
dramatic conformational changes before and after binding to the
molecular species and mediate molecular transport via an
intermittent transport pathway. In contrast, channel molecules
form a well-defined transmembrane pathway that is open to both
the intra- and extracellular environments, thus enabling
molecules to rapidly diffuse through membrane without
interruption. We describe here an alternative swing mechanism
for achieving exceptionally efficient ion transport. This swing
mechanism blurs the boundaries between carrier and channel
mechanisms, i.e., similar to carriers, molecular swings are not
simultaneously open to both the intra- and extracellular
environments. Like channels, molecular swings do follow a
defined pathway for facilitated molecular transport.
b)
PEG-C5: n = 1
PEG-C6: n = 2
MS-PEG
Our design of molecular swing is largely inspired by the recent
burgeoning development on artificial molecular machines,[3]
which attempt to mimic macroscopic functions using molecules
at the microscopic level. Researching novel molecular machines
is an active area at the forefront of chemical sciences, with the
2016 Nobel Prize in Chemistry awarded to Jean-Pierre
Sauvage,[4a] Sir J. Fraser Stoddart[4b] and Bernard L. Feringa.[4c]
Despite the availability of diverse types of molecular machines
for performing versatile functions seen in the macroscopic world
Figure 1. a) Chemical structures of molecular swings MS-C5 and
MS-C6, which carry four essential structural elements among which
lag bolts allow the swings to anchor into the hydrophilic membrane
regions and swing seat for binding and transporting metal ions; for
computationally optimized structure of MS-C5, see Figure S1. b)
Three control compounds PEG-C5 and PEG-C6, which contain only
components of PEG rope and swing seat, and MS-PEG, which
carries three components except for swing seat, for comparison with
MS-C5 and MS-C6 for the ion transport activities.
[*] Dr. C. Ren, Dr. F. Chen, Dr. Y. S. Ong, Dr. S. S. Lee and Dr. H. Zeng
Institute of Bioengineering and Nanotechnology
31 Biopolis Way, The Nanos, Singapore 138669
E-mail: hqzeng@ibn.a-star.edu.sg
(e.g. rotors,[5a-e] synthesizers,[5f,5g] pumps,[5h,5i] muscles,[5j,5k]
walkers,[5l] movers[5m]), the corresponding applications in
facilitating molecular transport across membrane have remained
essentially unexplored. The only example we are aware of uses
Ms. R. Ye
Department of Chemical and Biomolecular Engineering
National University of Singapore, Singapore 117585
a
molecular rotaxane to transport ions via a shuttling
mechanism[6]. Having an EC50 value of only 1.0 μM (3.0 mol%
relative to lipid), its activity is very low.
Dr. C. Ren, Dr. F. Chen, Dr. H. Lu, Prof. Dr. J. Y.-R. Ying and Dr. H.
Zeng
NanoBioLab, 31 Biopolis Way, The Nanos, Singapore 138669
In line with our long-standing interests in membrane
transporters[7] and stimulated by the macroscopic swings, one of
the simplest and perhaps most fun outdoor activities for kids, we
wonder whether we could build similar objects at the molecular
Supporting information for this article is available on the WWW under:
http://www.angewandte.org or from the author.
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10.1002/anie.201901833
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COMMUNICATION
a)
b)
1.0
0.8
0.6
0.4
0.2
0.0
pH = 8
M
‖
100 mM NaCl
MS-C5
100 mM KCl
1.0
0.8
0.6
0.4
0.2
0.0
MS-C5
MS-C6
98%
92%
81%
M+
100 mM MCl
Li+
Na+
K+
84%
MS-C6
H+
Rb+
Cs+
MS-PEG
(7%)
MS-PEG
(9%)
pH = 7
100 mM
[Channel] = 1 M
[Control] = 5 M
[Channel] = 1 M
[Control] = 5 M
PEG-C5
(8%)
PEG-C6
(8%)
PEG-C5
(9%)
HPTS
PEG-C6
(8%)
Blank (6%)
Blank (6%)
0
100
200
300
0
100
200
300
HPTS Assay
Time (s)
Time (s)
c)
d)
0.8
0.6
0.4
0.2
0.0
250
200
150
100
50
0.8
100 mM MCl
100 mM MCl
For MS-C5
KCl (72%)
KCl (68%)
[MS-C6] = 250 nM
Cs+
[MS-C5] = 80 nM
0.6
0.4
0.2
0.0
NaCl (56%)
Li+
Na+
NaCl (39%)
RbCl (39%)
Rb+
LiCl (27%)
LiCl (23%)
RbCl (16%)
CsCl (15%)
RbCl (15%)
+ (46 nM)
K
0
-500
-400
-300
0
100
200
300
0
100
200
300
G
hyd
(kJ/mol)
Time (s)
Time (s)
Figure 2. The pH-sensitive HPTS assay and measured ion transport activities and selectivities for molecular swings MS-C5 and MS-C6. a)
Schematic illustration of the HPTS assay for evaluating ion transport activities. b) Ion transport activities by MS-C5 and MS-C6 at 1 M and
three control compounds MS-PET, PEG-C5 and PEG-C6 at 5 M. c) Ion transport selectivities by MS-C5 at 80 nM and MS-C6 at 250 nM. D)
EC50 values for transporting alkali metal ions by MS-C5.
level, with swing function to operate within the context of cell
membrane. As illustrated in Figure 1a, analogous to the
macroscopic swing, the nanoscale-sized molecular swing was
designed to contain all four essential structural elements with
appropriate dimensions, i.e., two hydroxyl-rich cholesterol
groups as the lag bolts (or lipid anchors), one linear hydrazide
segment as the cross-beam, one flexible PEG chain as the rope
and one crown ether as the swing seat. The two lag bolts allow
the molecular swing to firmly anchor into the hydrophilic
membrane regions that serve as the support beams. A minor
difference does exist between the macroscopic and molecular
swings: while the former swings in the direction perpendicular to
the cross-beam, the swing direction in the latter is expected to
be mostly parallel to the cross-beam. The ability of the crown
ethers to bind Na+ and K+ ions should endow these artificial
molecular swings with the ability to swing ions across membrane
in the presence of an ionic concentration gradient.7b
To evaluate the hypothesis regarding the swing mechanism,
two molecular swings containing 15-crown-5 (MS-C5) or 18-
crown-6 (MS-C6) units as the swing seat were synthesized.
Their ion transport activities were assessed using the well-
established 8-hydroxypyrene -1,3,6-trisulfonic acid (HPTS). In
this assay, a pH-sensitive HPTS dye whose fluorescence
increases with increasing pH was placed inside egg yolk L-α-
phosphatidylcholine (EYPC)-based large unilamellar vesicles
(LUVs) to monitor ion transport-induced changes in
intravesicular pH and fluorescence intensity of HPTS dye
(Figure 2a). With a a pH gradient of 7 to 8 applied across LUVs,
high ion transport activities recorded over a period of 300 s were
always accompanied by large increments in ratiometric value of
HPTS fluorescence at 460 and 403 nm. After subtracting the
background intensity, the ratiometric values were further
normalized with that induced by Triton X-100 (added at t = 300
s) set as 100%, and used to gauge the ion transport ability of ion
transporters in terms of fractional transport activity.
Using this assay, both designed molecular swings (MS-C5 and
MS-C6) display distinctively high efficiencies of 81–98% in
transporting Na+ and K+ ions at a low concentration of 1 M
(Figure 2b). In sharp contrast, ion transports of either Na+ or K+
ions by the three control compounds, i.e., MS-PEG that lacks a
swing seat as well as PEG-C5 and PEG-C6 that contain only a
swing seat and a flexible PEG chain, are negligible even at a
high concentration of 5 M with respect to the background
signals. Similarly, a control compound (C14-Crown 5, Figure
S6), bearing a hydrophobic C14H29 chain, shows very low
activities with EC50 values of 23.9 M and 10.1 M for Na+ and
K+ ions, respectively.
Interestingly, although ion transport activities toward both Na+
and K+ ions differ only slightly between MS-C5 and MS-C6 at 1
M, such activities decrease more sharply for MS-C6 than MS-
C5 at lower concentration ranges. More specifically, MS-C5 at
just 80 nM could transport K+ ions as fast as MS-C6 at 250 nM
(Figure 2c). More detailed studies of varying extravesicular alkali
metal salts MCl (M+ = Li+, Na+, K+, Rb+ and Cs+) demonstrate
that MS-C5 is not only more capable but also more selective in
transporting K+ ions across membrane than MS-C6. Using the
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COMMUNICATION
c)
b)
a)
10 s
200 mM NaCl
Cl-
pH = 8
100 mM KCl
180 mV
10 pA
-
K+
NO3
140 mV
120 mV
0 mV
H+
200 mM
NaNO3
pH = 7
100 mM
FCCP
-100 mV
-140 mV
SPQ
HPTS
[FCCP] = 1 nM
[MS-C5] = 100 nM
e)
d)
1.0
0.8
0.6
0.4
0.2
0.0
1.0
0.8
0.6
0.4
0.2
0.0
Blank
Current (pA)
6
6.1 pA
15000
12000
9000
6000
3000
0
MS-C5 (200 nM)
MS-C5 + FCCP
4
2
74%
57%
MS-C5
FCCP
L8 (1 M)
0
0
-200
-100
100
200
Voltage (mV)
-2
-4
-6
9%
L8
Blank (6%)
300
0
100
200
0
100
200
300
0
2
4
6
8
10
γK+ = 29.4 ± 1.5 pS
Time (s)
Time (s)
Current (pA)
Figure 3. Deciphering the ion transport mechanism and determined single-channel conductance value for MS-C5-mediated transport of K+
ions. a) SPQ assay, demonstrating that MS-C5 does not transport chloride anions. b) Carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone
(FCCP)-based HPTS assay, showing that K+ ions are transported faster than H+ ions. c) Single-channel current traces recorded at various
voltages in symmetric baths (cis chamber = trans chamber = 1 M KCl) for MS-C5. d) Point amplitude histogram for all the recorded digitized
current values that gives a mean value of 6.1 pA at 180 mV. (For averaged current values and hitstograms at other voltages, see Figure S9).
e) Linear current–voltage (I–V) plot that yields a K+ conductance value (γK) of 29.4 ± 1.5 pS for MS-C5.
Hill analysis, the EC50 values at which transporters reach 50%
ion transport activity were determined to be 141, 110, 46, 108
and 207 nM for Li+, Na+, K+, Rb+ and Cs+ ions, respectively, for
MS-C5 (Figures 2d, S2 and S3). For comparison, EC50 values
for transporting Na+ and K+ ions are 172 and 101 nM for MS-C6
(Figure S4), and 2.91 M and 101 nM for valinomycin (Figure
S5). At the EC50 value of 46 nM, a channel:lipid molar ratio was
calculated to be 1:4800 (or 0.021 mol% relative to lipid),
signifying the extremely active nature of MS-C5-mediated
transport of K+ ions. Remarkably, these ion transport activities
remain high in lipids containing 33 mol% cholesterol, with EC50
values of 130 nM (0.045 mol% relative to lipid/cholesterol) and
326 nM for K+ and Na+ ions, respectively (Figure S7).
To ascertain that the observed ion transports did result from
ion-transporting function of these molecular swings, rather than
from their possible membrane-lysing activity, carboxyfluorescein
-leakage assay (ex = 492 nm, em = 517 nm) was conducted
(Figure S8). Melittin, which is able to form a pore of > 1 nm (a
size that is larger than carboxyfluorescein) in membrane or
efficiently lysate the membrane at low concentrations, cause
large increases in fluorescence by 59% and 92% at 100 nM and
200 nM, respectively, while MS-C5 produces a mere change of
2% at 1 M. These comparative data conclusively establish
membrane integrity in the presence of molecular swing MS-C5.
Next, chloride-sensitive SPQ dye (6-methoxy-N-(3-sulfopropyl)
quinolinium) was introduced into the assay, with intravesicular
region containing 0.5 mM SPQ dye and 200 mM NaNO3, and
extravesicular region containing 200 mM NaCl (Figure 3a). In
contrast to anion channel L8[7b] that results in fluorescence
quenching of SPQ by 46% at 1 M, no detectable fluorescence
quenching is observed with MS-C5, indicating that the latter is
incapable of transporting anions such as chlorides along its
linear backbone composed of lag bolts and a hydrazide segment.
These results support the H+/M+ antiport as the main transport
species by MS-C5. Similar results are also observed for MS-C6
(Figure S9a).
To compare the relative transport rates of K+ and H+ ions, the
HPTS assay was performed with extravesicular KCl at 100 mM
in the presence of a potent proton carrier FCCP (Figures 2a and
3b). If transport rate of H+ is much slower than that of K+, FCCP
will help to increase the transport rate of H+ to accompany the
molecular swing-mediated rapid influx of K+, giving rise to a
significant increase in fluorescence intensity. Experimentally, we
did observe a net increase of 17% between transport activities
mediated by MS-C5 alone (74%) and MS-C5 in the presence of
FCCP (57%). This increase, when compared to a small change
of 3% between FCCP along and background signal, is
significant enough for one to conclude that K+ ions are
transported much faster than H+ ions. Replacing extravesicular
KCl with NaCl generates similar results, similarly supporting that
Na+ is transported faster than H+ (Figure S9b).
As discussed above, molecular swing-mediated ion transport
follows a more defined pathway than a carrier, but more ill-
defined than an ideal channel that exhibits only a single level
conductance. To gain some insights into the mechanism (e.g.,
carrier or channel) how molecular swing transports K+ ions, we
recorded single-channel current traces in a planar lipid bilayer in
symmetric baths (cis chamber = trans chamber = 1 M KCl).
Observations of single-channel current traces at various
voltages unambiguously confirm that molecular swing MS-C5
behaves like
a single channel in swinging ions across
membrane (Figure 3c). As expected, numerous sublevel
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current values vs. number of occurrences, point amplitude
histograms were generated based on which a mean current
value could be obtained (Figure 3d). Using these histograms, we
obtained a mean value of 6.1 pA for channel currents recorded
at 180 mV (Figure 3d; for mean values at other voltages, see
Figure S10). Linear fitting of current-voltage (I-V) curve gives a
K+ conductance value (γK+) of 29.4 ± 1.5 pS (Figure 3E). This
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highly efficient transport of 1.8 x 107 K+ ions/s at 100 mV.
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The highly efficient molecular swing-mediated transmembrane
transport of K+ ions encouraged us to further investigate possible
uses of MS-C5 and MS-C6 in cancer chemotherapy. As the
most aggressive primary brain tumor, glioblastoma expresses a
variety of ion channels, with expression level of large
conductance K+ channels shown to positively correlate with the
tumor malignancy grade.[8a] These K+ channels are crucial in
buffering extracellular K+ ions for neuronal homeostasis as over-
accumulation of K+ ions in the extracellular space results in
depolarized neurons, which become less capable or even
incapable of firing action potentials. Following a standard cell
culturing protocol, the IC50 values of MS-C5 and MS-C6 toward
human primary glioblastoma cell line (U-87 MG, ATCC) were
determined to be 60 ± 1.4 M and 45 ± 0.6 M, respectively
(Figure S11). This suggests significant anticancer activities of
the molecular swings. In comparison, K+ channel blockers
including quinidine mostly display IC50 values of ~ 60 M and
above toward U-87 MG cell lines.[8b]
In summary, we have conceptually proposed and
experimentally verified a novel molecular machine-inspired
swing mechanism for promoting highly efficient transmembrane
flux of K+ ions. While operating in a single channel-like fashion,
this class of molecular swings does not have a single well-
defined ion permeation pathway to follow. Instead, ion transport
is mediated through numerous pathways, with an averaged
performance in potassium transport that is 27% better than
gramicidin A. Such highly active potassium transport helps to
deliver good IC50 values of 60 and 45 M, respectively, for MS-
C5 and MS-C6 toward brain tumor U-87 MG. Further structural
optimizations might lead to higher anticancer activities. Given
currently available varied types of molecular machines with
ranging and emerging functions, our strategy demonstrated here
may capture the imagination and attention of others in creating a
broad variety of “motional” channels with single-channel
behaviors as well as high activity and selectivity in
transmembrane transport. Besides breaking new grounds
scientifically, these motional channels may lead to practical
medical benefits in the future.
Acknowledgements
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This work was supported by the Institute of Bioengineering and
Nanotechnology and the NanoBio Lab (Biomedical Research
Council, Agency for Science, Technology and Research,
Singapore).
Keywords: Supramolecular chemistry · Synthetic ion channel ·
Molecular machine · Molecular Swing
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