Molecular Ion Fishers as Highly Active and Exceptionally Selective K+ Transporters

Article abstract of DOI:10.1021/jacs.9b04096

We report here a unique ion-fishing mechanism as an alternative to conventional carrier or channel mechanisms for mediating highly efficient and exceptionally selective transmembrane K⁺ flux. The molecular framework, underlying the fishing mech

Full text of DOI:10.1021/jacs.9b04096

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Communication
Molecular ion fishers as highly active and
exceptionally selective K+ transporters
Ruijuan Ye, Changliang Ren, Jie Shen, Feng Chen, Ning Li, Arundhati Roy, and Huaqiang Zeng
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b04096 • Publication Date (Web): 11 Jun 2019
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Molecular ion fishers as highly active and exceptionally selective
K transporters
+
†,丄
‡ ,丄
‡
‡
‡
‡
,‡
Ruijuan Ye, Changliang Ren,
Jie Shen, Ning Li, Feng Chen, Arundhati Roy and Huaqiang Zeng*
1
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†
College of Chemistry and Bioengineering, Hunan University of Science and Engineering, Yongzhou, Hunan, China 425100
The NanoBio Lab, 31 Biopolis Way, The Nanos, Singapore 138669
‡
a)
b)
ABSTRACT: We report here a unique ion-fishing mechanism
as an alternative to conventional carrier or channel mechanisms
for mediating highly efficient and exceptionally selective
transmembrane K flux. The molecular framework, underlying
9 Å
+
the fishing mechanism and comprising a fishing rod, a fishing
line and a fishing bait/hook, is simple yet modularly modifiable.
This feature enables rapid construction of a series of molecular
ion fishers with distinctively different ion transport patterns.
While more efficient ion transports are generally achieved by
using 18-crown-6 as the fishing bait/hook, ion transport
MF5-C8: m = 1, n = 1
MF6-C8: m = 1, n = 2
MF5-C10: m = 3, n = 1
MF6-C10: m = 3, n = 2
MF5-C12: m = 5, n = 1
MF6-C12: m = 5, n = 2
MF5-C14: m = 7, n = 1
MF6-C14: m = 7, n = 2
+
+
selectivity (K /Na ) critically depends on the length of the
21 - 27 Å
fishing line, with the most selective MF6-C14 exhibiting
+
+
exceptionally high selectivity (K /Na = 18) and high activity
EC50 = 1.1 mol% relative to lipid).
(
A
rtificial molecular machine is a rapidly developing science that
1-11
often takes a cue from macroscopic objects.
Recent years have
6 Å
seen a range of fascinating molecular machineries, performing
macroscopic functions at the molecular level. Notable examples
MF5-C10
1
2
3
3,4
5
include molecular muscle, shuttle, switch, rotor, propeller,
6
7
8
9
10,11
12
c)
pump, walker, mover, nanocar, synthesizer
and balance.
Awarding of the 2016 Nobel Prize in Chemistry to Jean-Pierre
1
2
3
Sauvage, Sir J. Fraser Stoddart and Bernard L. Feringa
undoubtedly will catalyze the field to a new height in both
fundamental and practical settings.
Step 1
Ion catch)
Step2
(Line rolling)
(
Although these recent burgeoning scientific advances in
molecular machines have greatly increased our ability to precisely
manipulate requisite molecular motions and macroscopic
functions at the molecular level, researching novel membrane-
active molecular machines has lagged far behind. Recently, Zhu
and his colleagues reported an interesting example of a rotaxane-
Catch-and-Release
Ion-Fishing Cycle
Membrane
central line
+
derived molecular ion shuttle, non-selectively transporting K
ions via a shuttling mechanism with moderate activity (EC = 3
5
0
1
3
mol% relative to lipid). We also elaborated a molecular swing
mechanism for swinging ions across membrane in a highly
efficient but weakly K -selective manner. Differing from
Step 3
(Ion release)
+
14
1
5-19
20-31
commonly seen carrier
and channel
mechanisms, these
Step 4
(Back to action)
13,14
alternative ion-shuttling and -swinging mechanisms
suggest
that unconventional ion transport mechanisms could also work
properly in membrane environment.
Herein, we disclose another unconventional ion-fishing
mechanism for delivering highly active and exceptionally
Figure 1. a) Molecular design of ion fishers MF5s and MF6s. b)
Computationally optimized structure of MF5-C10 at the B3LYP/6-31G*.
level. c) Proposed catch-and-release ion-fishing mechanism for fishing
ions across membrane.
+
selective transport of K ions. Despite their simple structure and
+
ease synthesis, a number of these ion fishers are highly K -
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selective, with the most selective MF6-C14 transporting K ions
a)
pH = 8
00 mM MCl
+
+
+
three times as fast as the complex and non-selective rotaxane-
based ion shuttle, and with an exceptional K /Na selectivity of
18 seven times that of the molecular swing (K /Na = 2.4).
These ion fishers therefore are among the most selective K
In fact, the highest unambiguously determined
K /Na selectivity of 9.8 was achieved only in 2017 through a
combinatorial screening.
We have a long interest in developing novel membrane-active
M = Li , Na , K
1
1
3
+
+
+
+
+
+
Rb , Cs
H
M
+
+
14
+
3
2-36
transporters.
+
+
Alternative mechanisms
pH = 7
00 mM NaCl
3
7
+
-
1) M /OH symport
1
-
-
2) OH /Cl antiport
1
4,37-40
HPTS
transporters.
Inspired by the popular angling fishing method
+
-
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7
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9
0
3
) H /Cl symport
where recreational fishers use a combination of fishing tackles to
catch fish, we designed a series of molecular ion fishers (MFs),
performing a catch-and-release ion-fishing function within the
context of lipid membrane. Structurewise, we covalently integrate
three essential and modularly tunable types of fishing tackles (e.g.,
fishing rod, fishing line and fishing bait/hook) with appropriate
dimensions into nanometer-sized MFs. The combined
hydrophobic length (30 - 36 Å, Figure 1a) matches a typical
hydrophobic membrane thickness (34 Å). Serving as the lipid
anchor to firmly anchor the MFs into one side of the membrane
region, the hydroxyl-rich cholesterol group with a rigid and linear
backbone also functions as a rigid fishing rod to orient both the
flexible alkyl chain-based fishing ropes of 21 - 27 Å and a crown
ether-based fishing bait/hook mostly in parallel with the
hydrophobic lipid tails. Energetically, the computationally
optimized linear conformation is at its thermodynamically most
stable state (see MF5-C10, Figure 1b).
Apparently, the catch-and-release fishing activity should take
place in four sequential steps (Figure 1c). First, the MF in a fully
extended state catches an ion through its fishing bait/hook from
one side of the membrane. Driven by an ion concentration
gradient, it curls up to allow the ion to cross the central line of the
hydrophobic membrane region in step 2. After some further
upward movement toward the membrane-water interface, it
releases the ion to the other side of the membrane in step 3, and
returns to its most stable extended state in step 4 to start another
ion-fishing cycle. Since the ion experiences the most pronounced
energetic penalty in the center of the hydrophobic membrane
region, the ability of MFs to overcome such resistance and bring
the ion to cross the membrane central line determines whether the
proposed fishing mechanism could work in lipid membrane or not
and the ion-fishing efficiency.
b)
1.0
0.8
0.6
0.4
0.2
0.0
1
00 mM KCl
[
MFs] = 2.0 µM
MF6-C8 (82%)
[
MF5-C14] = 20 M
MF5-C10 (64%)
MF6-C12 (49%)
MF6-C14 (41%)
MF5-C12 (37%)
MF6-C10 (34%)
MF5-C8 (28%)
MF5-C14 (9%)
Blank (3.4%)
0
150
300
Time (s)
+
Figure 2. a) pH-sensitive HPTS assay for ion transport study. b) K
transport curves for various MFs. RK = (IK – I0)/(ITriton– I0)
+
+
Although ratio of EC50 values is a widely used parameter for
comparing ion transport selectivity, they might not be sufficiently
accurate when transporters (1) have a poor solubility, (2)
experience self-aggregation or unfavorable interactions with lipids
or (3) form a multi-molecular channel whose active components
do not increase proportionally with the increased concentrations.
For instance, MF6-C12, requiring an un-obstructed large space
for proper function via an ion-fishing mechanism, may find
surrounding environment over-crowded at high concentrations.
+
+
That is, are these two ion fishers, having high K /Na selectivity
of > 28 estimated from the EC50 values, truly so K -selective?
+
To alleviate these possible issues, we previously used highly
+
K -selective 5F8 (Figure S6) as the reference channel and
+
K
+
To examine the applicability and efficacy of the hypothetic ion-
fishing mechanism, we designed two sets of MFs, containing 15-
crown-5 (MF5) or 18-crown-6 (MF6) units as the fishing
bait/hook, respectively, with the fishing line tuned from C H to
proposed the use of ratio of R
reliable index for selectivity assessment. In our previous work,
5F8 was unambiguously determined to have K /Na selectivity of
9.8 using single-channel current measurements, with ratios of 4.5
/RNa as a complementary and
37
+
+
8
16
+
+
+
+
+
C H . Using the pH-sensitive HPTS assay (Figure 2a), K ions
and 14.7 for EC50 (Na )/EC50 (K ) and R /RNa , respectively.
K
14
28
+
are found to transport faster than Na ions by most MFs, with
MF6-C8 displaying the highest transport activity (Figure 2b).
While MF6-C8 at 2.5 µM and MF6-C14 at 10 µM achieve RK
values of > 93%, the RK values of < 6% for all control
compounds (FR-C8, FR-C10, C5 and C6, Figure S1c) at 10 µM
are comparable to the background signal (3.4%).
The Hill analyses were conducted to determine EC values for
Na and K ions (Figures S2-S5 and Table 1). Six out of eight
MFs are found to be K -selective. MF5-C10, MF6-C8, MF6-
C12 and MF6-C14 exhibit both high activity (EC50 = 0.81 – 2.7
µM = 0.37 – 1.2 mol% relative to lipid) and high selectivity
In this work, we found that membrane dialysis method, rather
than flash column chromatography, to separate the excessive un-
encapsulated HPTS from LUVs consistently produces LUVs that
exhibit low background signals of 3 – 8% (Figure S7). Using
these tight LUVs, the EC50 (K ) of 5F8 was re-determined to be
5.2 µM (Figure S6), which is similar to previously determined 5.5
µM. Importantly, at [5F8] = 11 µM where 5F8 elicits a R
K
value of 92.3%, R
which is nearly identical to the absolute K /Na selectivity of 9.8.
This suggests ratios of R /RNa determined using LUVs with low
K
+
+
+
3
7
+
5
0
+
+
+
+
/RNa was determined to be 9.6 (Figure S8),
K
+
+
+
+
+
background signals allows ion selectivity to be gauged reliably
even though it still may differ from the true ion selectivity.
To obtain meaningful R values (R , RNa , etc) and ratio R
M K
+
+
(
K /Na > 7), and MF5-C12 and MF5-C14 are weakly active but
+
+
+
+
Na -selective.
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Table 1. Determined values for EC50 (M), EC50 (Na )/EC (K ) and R +/RNa+
+
+
.
50
K
MF5-C8
MF5-C10
MF5-C12
MF5-C14
MF6-C8
MF6-C10
MF6-C12
MF6-C14
+
a
EC50 (Na )
5.1 ± 0.2
4.6 ± 0.3
10.1 ± 0.2
1.4 ± 0.1
30.9 ± 2.9
>> 30
55.9 ± 1.7
>> 70
10.1 ± 0.8
0.81 ± 0.1
4.6 ± 0.2
2.7 ± 0.1
49.2 ± 3.4
1.7 ± 0.1
>> 70
+
a
EC50 (K )
2.5 ± 0.1
+
EC50 (Na )
1
.1
7.2
< 1
1.8
< 1
0.3
12.5
7.1
1.7
1.4
28.9
7.8
> 28
18.0
+
EC50 (K )
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9
0
+
+ b
RK /RNa
1.1
5.2
a
b
[
Total lipid] = 219 µM. See Figure S9 for more detail.
+
+
(e.g., RK /RNa ) for a reliable comparison of ion selectivity, it is
imperative to determine RM at the concentration where the
channel’s transport activity has been maximized to > 90% or
reached saturation over 300 s for the most active ion (Figures 3a
and S9). Following this criterion, we have obtained all R values
M = Li , Na , K , Rb and Cs ) for all eight MFs (Figure S9),
a)
1
.0
.8
+
100 mM MCl
KCl (93.7%)
[MF6-C14] = 10 M
0
CsCl (75.5%)
+
M
0.6
0.4
0.2
0.0
RbCl (54.9%)
+
+
+
+
+
(
+
+
with ratios of RK /RNa presented in Table 1.
+
As evidenced from R and ratio R values, seven out of eight
MFs are K -selective, including MF5-C12 otherwise shown to be
Na -selective using EC values. The most K -selective MF6-C14
displays exceptional K /Na selectivity of 18 (Figure 3a), yet with
high activity (EC50 = 2.5 µM or 1.1 mol% relative to lipid). MF6-
C8 (EC = 0.81 µM) and MF6-C12 (EC = 1.7 µM) also display
M
+
NaCl (5.2%)
LiCl (0.6%)
Blank (NaCl)
Blank (KCl)
+
+
5
+
0
+
0
150
300
Time (s)
5
0
50
b)
+
+
high K /Na selectivities of 7.1 and 7.8, respectively.
Interestingly, although MF5-C14 is weakly active, it displays
good Na /K selectivity of 3.6 and high selectivity against Rb
Na /Rb = 21) and Cs (Na /Cs = 65). More interestingly, all
eight MFs do not transport Li ions (Figure S9). This consistent
observation is in sharp contrast to our best knowledge that all
crown ether-based ion channels with ion transport activities tested
against Li ions all transport Li ions. This may imply that the
large dehydration energy of Li ions can’t be compensated for by
the crown ether unit that functions through a fishing mechanism,
but likely can be sufficiently compensated for by a channel
mechanism.
The M ions as the main transport species were established by
the chloride-sensitive SPQ assay (Figure 3b). Compared to anion
channel L8 that causes 65% fluorescence quenching of SPQ dye
at 3 M, that no significant fluorescence quenching by both MF6-
C8 and MF6-C14 was observed signifies the inability of MFs to
transport anions.
The transport rates between K and H were compared using a
proton carrier FCCP (Figure 3c). With respect to no change in
fluorescence intensity between FCCP alone and the background
signal, a net increase of 44% between transport activities
mediated by MF6-C14 in the absence (55%) and presence (99%)
of FCCP suggests K to be transported much faster than H .
Similar conclusion can be drawn for MF6-C8 (Figure S10).
The carboxyfluorescein-leakage assay (ex = 492 nm, em = 517
nm, Figure S11) shows that melittin, which forms a pore of > 1
nm or efficiently lysates the membrane at low concentrations,
results in large increases in fluorescence by 54% and 86% at 100
nM and 200 nM, respectively. In contrast, both MF6-C8 and
MF6-C14 produce changes of < 2% at 5 M. These results
support well-maintained membrane integrity in the presence of
MFs, ruling out the membrane-lysing activity of MFs.
200 mM NaCl
[Channle] = 3M
Blank (9%)
1
.0
.8
+
+
+
-
-
Cl
NO
3
+
+
+
+
+
0
(
MF6-C8 (12%)
MF6-C14 (10%)
+
0.6
L8 (65%)
0.4
0.2
0.0
2
00 mM
+
+
NaNO3
+
SPQ
0
100
200
300
Time (s)
+
c)
pH = 8
100 mM KCl
[MF6-C14] = 3 M
[FCCP] = 5 nM
1
.0
.8
.6
3
9
99%
+
K
+
H
MF6-C14 + FCCP
0
0
55%
+
+
MF6-C14
pH = 7
0.4
0.2
100 mM NaCl
FCCP
HPTS
FCCP = Blank
3
%
0
.0
0
100
200
300
+
+
Time (s)
+
Figure 3. a) Ion transport percentages (RM ) for MF6-C14 at 10 M. b)
SPQ assay to confirm the inability of MFs to transport anions. c) FCCP-
+
based HPTS assay to confirm that MF6-C14 transports K ions faster
+
than H ions.
Additional structure-activity-relationship studies on shorter
MF6-C2, MF6-C4 and MF6-C6 (Figures 4 and S12-S14) reveal
that the K transport activity peaks at MF6-C8 (EC = 0.81 µM),
with the highest K /Na selectivity achieved by MF6-C14.
+
5
0
+
+
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unprecedented among ion channels derived from crown ethers.
Further, it is believed that this class of ion fishers does not have a
single ion permeation pathway to follow. Rather, while operating
in a more carrier-like mechanism, they fish ions through
numerous pathways that are more defined than carriers but less
defined than channels. Given their highly modular nature and ease
synthesis, a broad range of molecular ion fishers can be readily
envisioned, possibly exhibiting outstanding membrane transport
properties for promising medical applications.
0
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16 Å
1
8 Å
ASSOCIATED CONTENT
2
1 Å
2
2 Å
Supporting Information. Synthetic procedures and a full set
1
13
of characterization data including H NMR, C NMR and MS as
well as a complete set of ion transport study. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
MF6-C2
Corresponding Author
MF6-C4
hqzeng@nbl.a-star.edu.sg
MF6-C6
+
EC50 (K ), M
MF6-R
Author Contributions
6
.6 ± 0.5
3.4 ± 0.3
5.7
1.4 ± 0.1
>> 40
丄
+
+
R.Y. and C.R. contributed equally to the work.
RK /RNa
5
.2
8.4
~ 1
ORCID
Huaqiang Zeng: 0000-0002-8246-2000
Figure 4. Structures and ion transport properties of the shorter (MF6-C2,
MF6-C4 and MF6-C6) and more rigid (MF6-R) MFs.
Notes
The authors declare no competing financial interest.
Further, from the stepwise analyses of catch-and-release ion-
fishing cycle (Figure 1c), this ion-fishing mechanism shares some
similarity with but also differs from carrier and channel
mechanisms. Like carriers, MFs are not simultaneously open to
both the intra- and extra-cellular environments. Like channels,
they do follow a defined pathway with one end fixed in the lipid
membrane through the cholesterol unit to facilitate ion transport
via a fishing mechanism. To examine to which of the two
mechanisms the ion-fishing mechanism is closer, we conducted
single-channel current measurements on MF6-C14. The fact that
our extensive efforts failed to record single-channel current traces
ACKNOWLEDGMENT
This work was supported by the NanoBio Lab (Biomedical
Research Council, Agency for Science, Technology and Research,
Singapore) and the construct program of applied characteristic
discipline in Hunan University of Science and Engineering
REFERENCES
(1) Sauvage, J.-P. From Chemical Topology to Molecular Machines
(Nobel Lecture). Angew. Chem. Int. Ed. 2017, 56, 11080-11093.
(2) Stoddart, J. F. Mechanically Interlocked Molecules (MIMs)—
Molecular Shuttles, Switches, and Machines (Nobel Lecture). Angew.
Chem. Int. Ed. 2017, 56, 11094-11125.
(3) Feringa, B. L. The Art of Building Small: From Molecular Switches
to Motors (Nobel Lecture). Angew. Chem. Int. Ed. 2017, 56, 11060-
11078.
suggests these ion fishers likely operate in
mechanism.
a carrier-like
Lastly, unlike the conventional ion carriers that can move freely
and randomly in both vertical and lateral directions, the MFs can
only move the same way laterally. More specifically, the rigid
cholesterol backbone, which acts as the lipid anchor, can’t move
vertically, with the remaining flexible part freely curling up or
down in a manner akin to a fishing process. Consequently, one
expects to see greatly diminished ion-fishing activity upon
replacing the flexible fishing rope with a rigid one that can’t bend.
We therefore prepared MF6-R rigidified by intramolecular H-
bonds (Figure 4). Consistent with the proposed ion-fishing
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