Combinatorial Evolution of Fast-Conducting Highly Selective K+-Channels via Modularly Tunable Directional Assembly of Crown Ethers

Article abstract of DOI:10.1021/jacs.7b04335

We describe here a modularly tunable molecular strategy for construction and combinatorial optimization of highly efficient K⁺-selective channels. In our strategy, a highly robust supramolecular H-bonded 1D ensemble was used to order the appended crown ethers in such a way that they roughly stack on top of each other to form a channel for facilitated ion transport across the membrane. Among 15 channels that all prefer K⁺ over Na⁺ ions, channel molecule 5F8 shows the most pronounced optimum for K⁺ while disfavoring all other biologically important cations (e.g., Na⁺, Ca²⁺ and Mg²⁺). With a K⁺/Na⁺ selectivity of 9.8 and an EC₅₀ value of 6.2 μM for K⁺ ion, 5F8 is clearly among the best synthetic potassium channels developed over the past decades.

Full text of DOI:10.1021/jacs.7b04335

Subscriber access provided by UNIV OF UTAH
Communication
Combinatorial evolution of fast-conducting highly selective K+-
channels via modularly tunable directional assembly of crown ethers
Changliang Ren, Jie Shen, and Huaqiang Zeng
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b04335 • Publication Date (Web): 24 Aug 2017
Downloaded from http://pubs.acs.org on August 24, 2017
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 5
Journal of the American Chemical Society
1
2
3
4
5
6
Combinatorial evolution of fast-conducting highly selective K+-channels
via modularly tunable directional assembly of crown ethers
7
8
Changliang Ren,† Jie Shen,† and Huaqiang Zeng*,†
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
† Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, Singapore 138669
c)
a)
b)
ABSTRACT: We describe here a modularly tunable molecular
strategy for construction and combinatorial optimization of
highly efficient K+-selective channels. In our strategy, highly
robust supramolecular H-bonded 1D ensemble was used to order
the appended crown ethers in such a way that they roughly stack
on top of each other to form a channel for facilitated ion
transport across the membrane. Among 15 channels that all
prefer K+ over Na+ ions, channel molecule 5F8 shows the most
pronounced optimum for K+ while disfavoring all other
biologically important cations (e.g., Na+, Ca2+ and Mg2+). With a
K+/Na+ selectivity of 9.8 and an EC50 value of 6.2 M for K+ ion,
5F8 is clearly among the best synthetic potassium channels
developed over the past decades.
R2
R3
R1
Fmoc-Phe-C4
d)
Natural ion channels are supremely elegant in structure and
particularly so in function. For instance, natural KcsA K+-channel
is at least 10,000 times more permeant to K+ than Na+ ions while
conducting K+ ions at an exceptional speed of 108 ions per
second.1 High selectivity in ion transport however currently
present a major challenge to the actively researched field of
artificially developed channel systems,2 and channels having very
moderate K+/Na+ selectivity of  10 still remain difficult to
develop.3a-c In constructing synthetic ion channels, crown ethers
are one type of privileged ion-transporting units that are featured
in many approaches. Examples include the hydraphiles by
Gokel,2f,2g as well as crowns conjugated to a peptide scaffold by
Voyer,2e,3d ferrocene units by Hall,3e a rigid rod-like molecule by
Matile3f and (thio)urea groups3b-c by Barboiu.
e)
Top view
H-bonded 6I8 (6-Ile-C8)
2 m
f)
2 m
We recently devised a monopeptide-based supramolecular
chiral synthon with a built-in H-bonding capacity, able to align
appended R1-R3 groups at the same side via an H-bonding-
mediated directional self-assembling process (Figure 1a-b).4a-c
Supported by the crystal structure of Fmoc-Phe-C4 (Figure 1b),4a
this synthon turns out to be highly robust in guiding molecular
packing into a predictable one-dimensionally aligned columnar
structure.4a-c Prompted by these findings, we thought that
modification of the H-bonded 1D network with ion-transporting
units such as 15-crown-5 or 18-crown-6 at the R1 position
(Figures 1c-e, S1 and S2, and Table S1) might lead to a new
family of ion channels such as 6I8 (6-Ile-C8), likely endowed
with ability to discriminate biologically important metal ions such
as Na+, K+, Ca2+ and Mg2+. One distinct trait of our system is its
intrinsic high modularity in backbone, enabling an evolutionary
approach with a parallel synthesis of library members to be
Gel formed by 5I8
Gel formed by 6I8
Figure 1. a) A supramolecular chiral synthon for aligning side chains of
the same type (e.g., R1-R3) at the same side. b) Crystal structure of Fmoc-
Phe-C4,4a demonstrating the ability of the synthon to form a H-bonded
1D columnar stack with R1-R3 aligned to the same side. The O and H
atoms involved in intermolecular H-bonds are highlighted as small red
and gray balls, respectively. c) Combinatorial diversifications at the R1
and R2 positions for discovering efficient and selective ion channels.
Molecules containing R2 = Gly = G were used to elucidate the importance
of chiral center in the self-assembling process. d) Structures of control
compounds. e) Top view of the computationally optimized most stable
structure of H-bonded 1D ensemble formed from 6I8 (Figure S2). f)
Gelation of a mixed solvent (hexane:toluene = 4:1, v:v) by 5I8 and 6I8
and the corresponding SEM images. The gels were visualized using
Sudan III.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 5
1
2
3
4
5
applied for rapid discovery of ion channels with good selectivity.
We firstly began with evaluation of 5I8 (5-Ile-C8) and 6I8
having an n-octyl side chain at the R3 position. Consistent with
a)
H+
pH = 8
100 mM MCl
Or
predictable ability to form
a H-bonded 1D structure via
6
7
8
9
intermolecular H-bonds, both 5I8 and 6I8 self-assemble into
well-defined fibers as evident from their ability to gel a mixed
solvent (hexane:toluene = 4:1, v:v) and from the images of the
dried gels obtained using scanning electron microscope (SEM,
Figure 1f) and transmission electron microscope (TEM) (Figures
S3-S6). The 1H NMR dilution experiments carried out by diluting
a solution containing 5I8 or 6I8 from 100 to 0.8 mM in CDCl3
reveal concentration-dependent chemical shifts for the two amide
protons involved in forming intermolecular H-bonds, additionally
supporting the formation of intermolecularly H-bonded 1D
structure (Figure S7). Biphasic extraction experiments using equal
volumes of H2O containing 7 metal ions (e.g., Li+, Na+, K+, Rb+,
Cs+, Ca2+ and Mg2+; each at 0.10 mM) in their nitrate salts and
CHCl3 containing an organic host (e.g., 15C5, 18C6, 5I8 or 6I8
at 0.70 mM) were carried out at 25 oC to determine their ion-
binding affinity and selectivity using inductively coupled plasma
mass spectrometry (ICP-MS). ICP data compiled in Table S2
show that all four ligands could extract Na+, K+ and Ca2+ ions to
similar extents, suggesting H-bonding network in 5I8 or 6I8 does
not noticeably interfere with the intrinsic ion binding ability of the
attached crown ether units. But do note that the observed
competitive ion extraction behaviors likely can’t be simply
extrapolated to what may happen in lipid membrane as ion
extraction extent and selectivity are strongly influenced by the
extraction solvent and the presence of other metal ions as recently
reported by Bartsch.5a-b
50 mM MCl2
pH = 7
100 mM NaCl
Mn+ = Li+, Na+, K+
Rb+, Cs+
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
HPTS
Ca2+, Mg2+
b)
140
120
100
80
5L8
5F8
5F10
Triton
6F8
6L8
60
6I8
5V8
6G8
40
5I8
5G8
18C6
15C5
20
Baseline
0
0
50
100
150
200
250
300
Time (s)
Figure 2. a) The HPTS-based assay for proton transport study using the
pH-sensitive HPTS (8-Hydroxypyrene-1,3,6-trisulfonic acid) trapped
inside lager unilamellar vesicles (LUVs) with a pH gradient of 7 to 8. To
determine ion selectivity, the external buffer was changed from 100 mM
NaCl to 100 mM MCl or 50 mM MCl2. b) Selected K+ transport curves at
a channel concentration of 22 M, illustrating progressively enhanced
transports of K+ ions upon fine-tuning R2 group. After subtracting
background intensity at t = 0, the ratiometric values of I460/I403 were
normalized with ratiometric value of I460/I403 at t = 0 s as 0% and that of
I460/I403 at t = 300 s (obtained after addition of triton) as 100%. For more
K+ and Na+ transports, see Figures S8-S11.
Indeed, ion transport activities assessed using the pH-sensitive
HPTS assay4d at a final channel concentration of 22 M over a
duration of 5 min (Figures 2 and 3) surprisingly demonstrate very
+
different Na+ and K+ transports across the membrane by 5I8 (RNa
+
+
+
= 6.1% and RK = 17%) and 6I8 (RNa = 6.4% and RK = 60%).5
In sharp contrast to 6I8, both the isolated crown ethers (e.g.,
15C5 and 18C6) and molecules containing a non-chiral center
(e.g., 5G8 and 6G8) exhibit very poor ion transport and low ion
selectivity (Figure 2b). These differential channel activities in ion
transport and selectivity suggest (1) important roles played by the
chiral center and built-in H-bonding motif in organizing crown
ethers into a functional assembly and (2) one dimensionally
aligned 18-crown-6 units could differ very substantially in
function from the ensemble based on 15-crown-5 motifs. As
illustrated in Table S1 and Figures S1 and S2, side chains of the
amino acids at the R2 position do modify the relative orientation
among the vertically aligned crown units, further highlighting the
those with 18-crown-6, and transport curves (5F8, 5F10, etc),
which exceed 100% after normalization, are indicative of high
K/Na selectivity where proton influx is more efficient that Na
influx at high concentration. While all four channels derived from
alanine and valine (5A8, 6A8, 5V8 and 6V8) turn out to be poor
+
+
ion conductors with the highest RNa and RK values being 11%
nd 34%, respectively, those based on leucine and phenylalanine
(5L8, 5F8 and 6F8) are highly active toward K+ ions with a RK
+
feasibility of using the monopeptide-based scaffold for
a
value going beyond 100% (Figure 2b), which corresponds to a
point where the internal pH was raised from 7 to larger than the
pH of external solution. In particular, 5F8-mediated K+ transport
is the fastest among all channels studied and is so fast that the
time needed for the internal pH to reach an equilibrium pH of 8
takes merely 25 sec. This extremely fast conduction suggests that
a RK+/RNa+ value of 2.5 at 22 M underestimate the ion selectivity
of 5F8. Expectedly, upon lowering the concentration from 22 M
down to 8.8 M at which a smoothly growing curve was obtained
combinatorial search of more selective and faster ion-conducting
channels.
A combinatorial screening was then attempted via synthesis of a
small library containing another eight crown ether-containing
channel molecules derived from alanine (A), valine (V), leucine
(L) and phenylalanine (F) with R3 = C8. At the same final
concentration of 22 M, a common trend shared by all channel
molecules is that they all transport K+ preferentially over Na+ ions
with RK+/RNa+ values ranging from 1.4 to 7.1 (Figures 2b and 3).5
As similarly observed by others,3b-c K+ transport generally appears
to be faster with channels containing stacked 15-crown-5 than
with 97% of K+ transfer completed in 5 min, the RK+/RNa value
+
was increased to 14.7 (Figure 4a).5c Similarly for 5L8, the
RK+/RNa value was determined to be 8.3 at 19.8 M (Figure
+
ACS Paragon Plus Environment

Page 3 of 5
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
100
80
60
40
20
0
Na+
K+
100
97
9
91
88
10
11
12
13
14
15
16
17
18
69
60
34
34
33
27
26
24
20
17
16
14
12
11
11
9.8
9.9
2.7
2.6
2.2
8.4
2.1
7.9
1.4
6.6
6.6
6.4
6.1
4.3
3.3
15C5 18C6 5G8 6G8 5A8 6A8 5V8 6V8 5I8
6I8 5L8 6L8 5F8 6F8 5F4 5F6 5F10
Figure 3. Ion transport percentages determined over a duration of 5 min at 22 M for all channel molecules except for 5L8 (19.8 M), 5F8 (8.8 M),
5F10 (5.5 M) and 6F8 (19.8 M). RK+ = (IK+ – I0)/(ITriton– I0) wherein IK+ and I0 (background intensity) are the ratiometric values of I460/I403 at t = 300 s
before addition of triton, and ITriton is the ratiometric value of I460/I403 at t = 300 s right after addition of triton with internal/external buffers containing 100
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
mM NaCl/100 mM KCl, i.e., (NaCl)in/(KCl)out. For RNa+, the internal/external buffers are (NaCl)in/(NaCl)out
.
a
)
b)
c
)
100
80
60
40
20
0
100
80
60
40
20
0
VA (0.02 M)
K+
K+
[Safranin O] = 60 nM
RK+/RNa+ = 10.0
RK+/RNa+ = 14.7
2.5
2.0
1.5
1.0
Rb+
VA/5F8/5F10
(NaCl out)
5F8 (5 M)
VA (0.32 M)
5F8
5F10
Rb+
5F10 (5 M)
RRb+/RNa+ = 7.4
RRb+/RNa = 7.7
+
VA (1.25 M)
+
+
Cs
Cs
+
+
RCs+/RNa+ = 1.6
Na
Na
RCs+/RNa+ = 2.1
+
+
Li
Li
VA (5 M)
2+
2+
Ca
Ca
2+
2+
Mg
Mg
Baseline
Baseline
VA/5F8/5F10/DMSO (KCl out)
0
100
200
300
0
50
100
150
200
250
300
350
0
100
200
Time (s)
300
Time (s)
Time (s)
Figure 4. Transport activities toward Li+, Na+, K+, Rb+, Cs+, Ca2+ and Mg2+ ions at a final concentration of (a) 8.8 M for 5F8 and (b) 5.5 M for 5F10,
respectively. c) Changes in fluorescence intensity of Safranine O (λex = 522 nm, λem = 581 nm; 60 nM) after addition of 5F8 and 5F10 at 5 μM and
Valinomycin (VA) from 0.02 to 5 μM. The 10 mM HEPES buffer at pH 7 inside LUVs contains 100 mM KCl while external HEPES buffer at pH 7
contains either 100 mM KCl or 100 mM NaCl. In c), the starting background intensity F0 at t = 0 was set to be 1.
+
S11c). In terms of both ion transport rate and selectivity, 5F8 is
considerably much better than the recently reported crown ether-
based K+-selective channels3b,3c the best of which requires a
(RK+/RNa = 10.0). The corresponding EC50 values (e.g., the
concentration required to attain 50% ion permeation) for K+ and
Rb+ ions are 6.2 and 9.4 M for 5F8 and 2.4 and 3.9 M for
5F10 (Figure S12), respectively. These comparisons in EC50 value
indicate that the longer C10 chains in 5F10 might enhance the
stability and/or increase the open probability of the H-bonded
channel structure in the membrane more significantly than the
shorter C8 chains do, particularly at low concentrations of < 6 M.
With an existence of a difference in ion concentration between
the interior and exterior of a LUV, selective ion transport will
lead to an accumulation of cations on one side of the membrane,
resulting in membrane polarization that can be analyzed using
Safranin O, a voltage sensitive dye. Upon changing the ion
concentration in the external buffer from 100 mM KCl to 100 mM
NaCl, both 5F8 and 5F10 at 5 M cause large changes in
fluorescence intensity by > 100% relative to the signal at t = 50 s
+
higher channel concentration of 25 M to reach a RK value of
100% but shows a low RK+/RNa+ value of only 6.7.3c
On the basis of 5F8, our secondary screening looked into the
impact the chain length of R3 group might have on the channel’s
performance. Our results show that channels 5F8 and 5F10
containing longer alkyl chains (e.g., C8 and C10, Figure 3) are far
more efficient and selective in ion transport than 5F4 and 5F6
with shorter ones. A more careful and systematic comparison
between 5F8 and 5F10 reveals (1) these two channels display a
similar trend in ion selectivity, i.e., their transport activities
decrease in the order of K+ > Rb+ >> Cs+ > Na+ > Li+ ≈ Ca2+
≈
+
Mg2+ and (2) the more selective 5F8 (RK+/RNa = 14.7)5c
transports K+ ions less efficiently than the less selective 5F10
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 5
1
2
3
4
5
a)
b)
AUTHOR INFORMATION
Gramicidin A
5F8
γK+ = 23.2 ± 0.4 pS
γK+ = 26.4 ± 2.8 pS
Corresponding Author
hqzeng@ibn.a-star.edu.sg
6
7
8
9
Notes
5 pA
The authors declare no competing financial interest.
5 s
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACKNOWLEDGMENT
Figure 5. Single channel current traces of (a) the dimeric gramicidin A
recorded at 200 mv and (b) 5F8 recorded at -200 mv, respectively, in
symmetrical solutions (cis chamber = trans chamber = 1 M KCl).
This work was supported by the Institute of Bioengineering
and Nanotechnology (Biomedical Research Council, Agency for
Science, Technology and Research, Singapore) and the Singapore
National Research Foundation under its Environment and Water
Research Programme and administered by PUB.
(Figures 4c and S13a-b). Compared to changes of 164% by
Valinomycin at 0.2 M (Figures 4c and S13c), < 10% by
gramicidin A (Figure S13d) and < 20% by other synthetic highly
selective K+ channels,3c such large degrees of membrane
polarization caused by 5F8 and 5F10 are very remarkable,
establishing highly selective transport of K+ ions.
Taken together, the above data demonstrate that 5F8 and 5F10
markedly outperform all other 13 channels studied herein, and
5F8 is the most selective in K+ transport among all. The ability of
5F8 to function as an ion channel rather than a carrier in
mediating ions across the membrane was then unambiguously
confirmed by the observation of single channel current traces
recorded in both symmetrical (cis chamber = trans chamber = 1
M KCl) and asymmetric (cis chamber = 1M KCl and trans
chamber = 1 M NaCl) baths (Figures 5b and S14d). On the basis
of I-V curves obtained (Figure S14a and c), potassium conduction
rate (γK+) and K+/Na+ selectivity were determined to be 26.4 ± 2.8
pS and 9.8, respectively, demonstrating that 5F8-mediated
transport of K+ ions occurs in a fast and highly selective fashion.
REFERENCES
(1) Doyle, D. A.; Morais Cabral, J.; Pfuetzner, R. A.; Kuo, A.; Gulbis, J.
M.; Cohen, S. L.; Chait, B. T.; MacKinnon, R. Science 1998, 280,
69.
(2) (a) Vargas Jentzsch, A.; Hennig, A.; Mareda, J.; Matile, S. Acc.
Chem. Res. 2013, 46, 2791; (b) Sakai, N.; Matile, S. Langmuir 2013,
29, 9031; (c) Montenegro, J.; Ghadiri, M. R.; Granja, J. R. Acc.
Chem. Res. 2013, 46, 2955; (d) Fyles, T. M. Acc. Chem. Res. 2013,
46, 2847; (e) Otis, F.; Auger, M.; Voyer, N. Acc. Chem. Res. 2013,
46, 2934; (f) Gokel, G. W.; Negin, S. Acc. Chem. Res. 2013, 46,
2824; (g) Gokel, G. W.; Mukhopadhyay, A. Chem. Soc. Rev. 2001,
30, 274; (h) Davis, A. P.; Sheppard, D. N.; Smith, B. D. Chem. Soc.
Rev. 2007, 36, 348; (i) Davis, J. T.; Okunola, O.; Quesada, R. Chem.
Soc. Rev. 2010, 39, 3843; (j) Zhao, Y.; Cho, H.; Widanapathirana,
L.; Zhang, S. Acc. Chem. Res. 2013, 46, 2763; (k) Gong, B.; Shao, Z.
Acc. Chem. Res. 2013, 46, 2856; (l) Si, W.; Xin, P.; Li, Z.-T.; Hou,
J.-L. Acc. Chem. Res. 2015, 48, 1612; (m) Huo, Y. P.; Zeng, H. Q.
Acc. Chem. Res. 2016, 49, 922.
(3) (a) Wright, A. J.; Matthews, S. E.; Fischer, W. B.; Beer, P. D. Chem.
Eur. J. 2001, 7, 3474; (b) Sun, Z.; Barboiu, M.; Legrand, Y.-M.;
Petit, E.; Rotaru, A. Angew. Chem., Int. Ed. 2015, 127, 14681; (c)
Gilles, A.; Barboiu, M. J. Am. Chem. Soc. 2016, 138, 426; (d) Otis,
F.; Racine-Berthiaume, C.; Voyer, N. J. Am. Chem. Soc. 2011, 133,
6481; (e) D. Hall, C.; J. Kirkovits, G.; C. Hall, A. Chem. Comm.
1999, 1897; (f) Sakai, N.; Gerard, D.; Matile, S. J. Am. Chem. Soc.
2001, 123, 2517.
(4) (a) Ren, C. L.; Ng, G. H. B.; Wu, H.; Chan, K.-H.; Shen, J.; Teh, C.;
Ying, J. Y.; Zeng, H. Q. Chem. Mater. 2016, 28, 4001; (b) Ren, C.
L.; Chen, F.; Zhou, F.; Shen, J.; Su, H. B.; Zeng, H. Q. Langmuir
2016, 32, 13510; (c) Ren, C. L.; Shen, J.; Chen, F.; Zeng, H. Q.
Angew. Chem., Int. Ed. 2017, 56, 3847. (d) Zhao, H. Q.; Sheng, S.;
Hong, Y. H.; Zeng, H. Q. J. Am. Chem. Soc. 2014, 136, 14270.
(5) (a) Bartsch, R. A.; Jeon, E.-G.; Walkowiak, W.; Apostoluk, W. J.
Memb. Sci. 1999, 159, 123; (b) Talanova, G. G.; Elkarim, N. S. A.;
Hanes, R. E.; Hwang, H.-S.; Rogers, R. D.; Bartsch, R. A. Anal.
In conclusion, we have established here
a privileged
monopeptide-based scaffold toward creation of K+-selective ion
channels via directional assembly of crown ethers. Characterized
by high tunability in structure and reliability in channel formation,
our channel system represents an unusual example among the
hitherto artificially developed ion channel systems. Accordingly,
the most advantageous feature of our approach is its intrinsic
modularity in appended side chains, which is mostly independent
of and thus exerts a tolerable degree of influences on the main
chain’s H-bonding functionality and self-assembling propensity,
thereby enabling consistent formation of crown ether-containing
H-bonded 1D structures. Such easily accessible tunability
subsequently allows a combinatorial optimization of channels’ ion
transport efficiency and selectivity, quickly giving rise to two fast-
conducting K+-selective channels (e.g., 5F8 and 5F10) that are
comparable to the best K+-selective channels described in
literature over the years.2,3
ASSOCIATED CONTENT
+
Chem. 1999, 71, 672; (c) Although the values of RM and ratio R
(e.g., RK+/RNa+) could be used to quickly and reliably gauge the
relative ion selectivity across different classes of channel molecules,
ratio R could only serve as a good approximation of true ion
selectivity intrinsic to any channel molecule (See Table S3 and
Figure S15 for a detailed discussion involving EC50 values). Instead,
the best approach to determine the ion selectivity is via the use of
single channel current measurement.
Supporting Information. Synthetic procedures and a full set
of characterization data including 1H NMR, 13C NMR and MS for
all channel molecules as well as ion transport study, single
channel current recording, molecular modeling, SEM/TEM
images, 1H NMR dilution experiments and ICP data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
ACS Paragon Plus Environment

Page 5 of 5
Journal of the American Chemical Society
1
2
3
Graphic for the Table of Contents
4
5
6
7
8
K+ Ca2+
Na+
Mg2+
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
K+
ACS Paragon Plus Environment