Calix[4]trap: A Bioinspired Host Equipped with Dual Selection Mechanisms

Zhenchuang Xu, Nie Fang, and Yanchuan Zhao*

Article

Calix[4]trap: A Bioinspired Host Equipped with Dual Selection

Mechanisms

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sı Supporting Information

ABSTRACT: Regulation of recognition events evolving in time and space is

vital for living organisms. During evolution, organisms have developed

distinct and orthogonal mechanisms to achieve selective recognition,

avoiding mutual interference. Although the merging of multiple selection

mechanisms into a single artiﬁcial host may lead to a more adaptable

recognition system with unparalleled selectivity, successful implementation

of this strategy is rare. Inspired by the intriguing structures and recognition

properties of two well-known biological ion bindersvalinomycin and K

channelswe herein report a series of hosts equipped with dual guest

selection mechanisms. These hosts simultaneously possess a preorganized

binding cavity and a conﬁned ion translocation tunnel, which are crucial to

the record-setting K /Na selectivity and versatile capabilities to

discriminate against a wide range of ion pairs, such as K /Rb , K /Ba ,

and Rb /Cs . Mechanistic studies verify that the host’s portal is capable of discriminating cations by their size, enabling varied ion

uptake rates. The conﬁned tunnel bearing consecutive binding sites promotes complete desolvation of ions during their inclusion

into the buried cavity, mimicking the ion translocation within ion channels. Our results demonstrate that the capability to manipulate

guest recognition both in equilibrium and out-of-equilibrium states allows the host to eﬀectively discriminate diverse guests via

distinct mechanisms. The strategy to merge orthogonal selection mechanisms paves a new avenue to creating more robust hosts that

may function in complex biological environments where many recognition events occur concurrently.

INTRODUCTION

single host? Could this act as new design wisdom to achieve

more versatile and record-setting discrimination ability? Here,

we implement this idea in developing a new class of

biomimetic hosts that we name calix[4]traps because of their

structural similarity to pitcher plant (Figure 1B). Calix[4]traps

■

Molecular recognitions ubiquitously occur in life activities.

Metal ions are vital to various physiological processes, ranging

from heartbeat and muscle contraction to signal trans-

−3

duction.

Through evolution, living organisms have mas-

tered the skill of selective binding and transporting ions by

creating task-oriented functional units. Prominent examples

include valinomycin and K channels, both of which allow for

ion traﬃcking across the cell membrane. Valinomycin

possesses a rigid scaﬀold and utilizes six carbonyl oxygens to

form an ion binding cavity (Figure 1A). The preorganized

structure along with the optimal cavity size account for its

much stronger aﬃnity to K than Na . In contrast, kinetic

possess record-breaking K /Na selectivity superior to

valinomycin and other artiﬁcial ion hosts, whereas their

conﬁned binding tunnel structurally mimics K channels,

enabling varied ion uptakes rates. The embedding of

orthogonal selection strategies renders calix[4]traps capability

to eﬀectively separate a variety of ion pairs, such as Na /K ,

K /Rb , K /Ba , and Rb /Cs via distinct mechanisms. The

unique structure of calix[4]trap allows the characterization of

ion translocation from the tunnel’s portal to the internal

binding cavity, serving as an ideal model to understand

successive recognitions in a conﬁned environment.

factors dominate in the selection mechanism of K channels, in

which ions are conducted at vastly diﬀerent rates. The

successive binding sites within the channel’s selectivity ﬁlter

constitute an ion transporting highway, where strict perme-

ation of K is not only dictated by the ion’s charge and radius

but also by the ease for the ion to undergo desolvation (Figure

−11

Received: November 23, 2020

Published: February 19, 2021

A).

These two examples demonstrate cases in which

nature achieves guest discrimination through manipulating

either binding aﬃnities or rates. Although bionic designs are

mostly directed to mimic one speciﬁc biological structure and

2−21

function,

we asked what if we combine the selection

strategies of valinomycin and K channels and realize them in a

2021 American Chemical Society

Journal of the American Chemical Society

J. Am. Chem. Soc. 2021, 143, 3162−3168

162

Article

Figure 1. Design and synthesis of calix[4]traps. (A) Valinomycin and the selectivity ﬁlter of K channel of streptomyces A (KcsA) (Protein Data

Bank, 1K4C). (B) Image of a pitcher plant, the structure of 1,3-alternate calix[4]crown-5 (1), and X-ray single-crystal structure of calix[4]trap 3a.

The picture of the pitcher plant was crafted by Ms. Suzhen Zhu. (C) The “ﬂip” and “lock” strategy used to synthesize the designed ion hosts.

Hydrogenation of double bond of 3a·K aﬀords 4a·K .

Inspired by the unique structure and properties of

valinomycin and K⁺channels, we sought to create a

biomimetic ion host that discriminates ions through both

thermodynamic and kinetic selection mechanisms. Given the

fact many ion hosts display excellent thermodynamic ion

only portal for ion uptake. We are also aware that a proper

linkage between the aromatic clefts is needed to restrain the

conformational ﬂexibility to prevent the opening of clefts. In

the re-engineered host 3a, the two methoxy groups on the

tunnel mouth along with the etheric oxygens of crown-5

constitute spatially consecutive binding sites that elongate into

the conﬁned internal space (Figure 1B, C). These structural

2,23

selectivity,

our eﬀort is directed to confer established ion

hosts with a tunnel-like ion transport path that is essential for

kinetically varied ion binding. We see the 1,3-alternate

calix[4]arenecrown-5 (1) as a great candidate on which to

perform the structural reengineering because it functionally

features resemble those of K channels and would enable

successive recognitions during the inclusion of the ion into the

buried cavity. Through this strategic modiﬁcation, we were

able to impart a host with the capability to kinetically

discriminate ions with minimal alteration of its original ion

binding environment.

resembles valinomycin and displays recording-setting K /Na

4,25

selectivity.

Unlike the orderly ion transport occurring

within ion channels, metal ions approach 1’s central cavity

from diverse directions, resulting in rapid and poorly

RESULTS AND DISCUSSION

controlled binding processes. Despite the exceptional K /Na

■

selectivity, 1 fails to eﬀectively discriminate K from metal ions

A “ﬂip and lock” strategy was utilized to prepare the target host

3a with binding sites wrapped around by molecular clefts

(Figure 1C). The synthetic route design is inspired by a

classical conformational switch observed in calixarene-based

of comparable sizes, such as Rb and Ba . We thus wonder

whether the not-yet-owned discrimination ability could be

conferred by a conﬁned binding tunnel biomimetic to K⁺

channel, where ions are uptaken with distinct rates. To test the

feasibility of this idea, we ﬁrst attempted to encapsulate 1’s

ligating etheric oxygens within a conﬁned tunnel to block the

original ion binding path. We envision that the extension of the

arene clefts on the calixarene’s lower rim would fully cover the

crown-5 motif from left and right, thereby preventing ions

from squeezing in from both sides (Figure 1B). Under this

circumstance, the calix[4]arene cavitand would become the

crown ethers upon K binding (Figure 1C), which is likely

driven by the favorable cation-π interactions proposed by

Prodi, Casnati, and co-workers. As depicted in Figure 1C,

compound 2a was ﬁrst mixed with K in acetonitrile to switch

to 1,3-alternate structure (Figure S5). Acetonitrile was then

replaced by dichloromethane to perform the subsequent ring-

closing metathesis (RCM), aﬀording 3·K⁺in ﬁxed con-

formation (Figure 1C). To gain more insights on the

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Figure 2. Ion recognition behaviors and ions separation experiments. (A) H NMR titration of calix[4]trap 3a with K in d -acetone. Two sets of

NMR signals corresponding to 3a and 3a·K were observed, suggesting that the exchange between free and bound K is slow on the NMR time

scale. (B) Measured log K (binding aﬃnity, in d -acetone/CDCl = 4:1 (v/v)) and log k (associating rate constant, in d -acetone/CDCl or

acetone/CHCl = 4:1 (v/v)) of 3a at 25 °C. (C) Separation of K , Rb , and Cs based on the distinct complexation rates. Ion compositions were

measured at diﬀerent times using ICP-MS. (D) Selective cation extraction using 3a in the presence of various cations. Hyphens indicate that the

concentration of the measured cation was lower than the limit of detection.

conformational ﬂipping and cation−π interaction in our

has a pronounced inﬂuence on the recognition of metal ions

because the binding is accompanied by the change in both ion

solvation state and electrostatic interactions between ion

system, we performed H NMR analysis of the binding

between 2a and K . As shown in Figure S5, upon the addition

of K to a solution of 2a, 2a underwent a conformational

pairs. To minimize the inﬂuence of anion and ensure a high

switch from the cone conﬁguration to mainly the 1,3-alternate

conformer. A pronounced downﬁeld shift of the resonance of

solubility of the metal salts under our experimental conditions,

−

we used the weakly coordinating C F SO as the counterion

H was observed, which supports the presence of the cation−π

for all the measurements. Competitive experiments with 1

interaction. The internal oleﬁn was mostly formed in the E-

conﬁguration during RCM, probably due to the lower ring

strain during cyclization (Figure 1C). We also attempted to use

shorter alkenyl chains for the RCM, whereas only oligomeric

revealed that 3a is 1.46 times stronger at binding with K and

3.16 times weaker at binding to Na ; the K /Na selectivity

increases by 4.61 times after the structural reengineering

(Figures S12 −14 ). A more rigidiﬁed binding environment

substances were produced. As the bound K is deeply buried,

could account for the high aﬃnity of 3a toward K , whereas

the attenuated aﬃnity to Na⁺is unexpected because an

the obtained 3a·K displays considerable stability, preserving

the trapped K during chromatographic puriﬁcation. In

increase in preorganization was envisioned to strengthen

contrast, the K of 2a·K is readily removed during the

binding to both K and Na . We assume that the isolated

binding cavity of 3a minimizes the energetically favored

interactions between the bound ion and species in the solvent,

which thereby leading to fewer ligating sites and inferior

aﬃnity after binding (Figures S15 and 16). This assumption is

workup, supporting the signiﬁcant contribution of shielding on

8,29

stability.

As expected, a signiﬁcant increase in K aﬃnity

was observed for all the calix[4]traps compared to that of

conformationally unﬂipped host 2a (Table S9 ). The metal-free

host 3a was then accessed by using cryptand[2.2.2] as the K⁺

scavenger in reﬂuxing acetonitrile wherein 3a precipitates out,

allowing for facile isolation. The X-ray single-crystal structure

of 3a veriﬁed a structure with consecutive and deeply buried

ligating sites. These structural features resemble those of the

selective ﬁlter of KcsA, where multiple carbonyl ligating groups

within the channel constitute an ion transporting highway.

Following the encouraging initial results, we next examined

also supported by the observation that 3a fails to bind Na in

the presence of an excess amount of water, whereas the aﬃnity

of 1 to Na only drops by about 2 times under the same

conditions (Figure S16). In analogy to K channels, calix[4]-

trap 3a is capable of harnessing distinct ion solvation

properties and conﬁned space to achieve better ion

discrimination. Our ﬁndings thus indicate that the modulation

of solvent accessibility to the binding pockets might be a viable

way to further boost the record-setting selectivity (for a list of

whether our design strategy retains the exceptional K /Na

selectivity of host 1. It is noteworthy that the nature of anion

K /Na selectivities of other ion hosts, see Table S10).

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Article

ring closure, shows substantial aﬃnities to Ba²⁺besides alkali

metal ions (Figure S8 ).

Considering that the K /Na selectivity in aqueous solution is

more relevant to biological applications, we attempted to

embed calix[4]trap 3a in liposomes following previously

reported methods. However, it was found that calix[4]trap

We next examined whether varied ion uptake rates and

negligible aﬃnity to alkaline-earth metal ions could confer 3a

unique separation properties. The separation system was

designed to take the advantage of the distinct solubility and

high kinetic stabilities of ion-complexed 3a and metal salts. In

one experiment, 3a was mixed with an acetone solution

a existed in the solid form under these conditions and was not

mixable with liposomes in water. This behavior is likely due to

the low solubility of 3a in both water and liposomes, which is

reasonable given the fact that 3a possesses a highly rigid

skeleton rich in aromatic rings. To test the K /Na selectivity

of calix[4]traps in an aqueous solution, where the K and Na

ions are highly hydrated, we performed a structural

modiﬁcation on 3a by replacing the methoxy group on the

tunnel mouth with a polyethylene glycol (PEG) chain. The

structurally modiﬁed calix[4]trap 3a-PEG, albeit not soluble in

pure water, possesses good solubility in d -acetone/D O (v/v

1/1), which allows the measurement of binding selectivity

toward hydrated K and Na . The investigation showed that

containing K , Rb , and Cs at low temperature and then

warmed to rt for ion complexation. The addition of

dichloromethane leads to the precipitation of unchelated

metal salts, which were readily separated from ion-complexed

3a through ﬁltration. We found the extraction selectivity is

dependent on the operation time, with the highest selectivity

(K:Rb > 99:1) observed when the precipitation was conducted

immediately after mixing. As the operation was prolonged to

allow ion exchange to occur, inferior extraction selectivity has

resulted. When the mixture was placed at rt for 96 h, the ratio

the K /Na selectivity of 3a-PEG in this solvent mixture is

higher than 1 × 10 , indicating that excellent K /Na

between 3a·K to 3a·Rb became 1.5:1(Figure 2C), verifying a

kinetically controlled ion uptake. By using a similar procedure

but without resorting to low operation temperatures, the

selectivity is retained in the presence of water (page S39 in

the Supporting Information). The high K /Na selectivity is

also supported by the mass spectroscopy experiments (Figure

S23 ), in which the mass signal related to [3a-PEG+Na] was

selective extraction of K from a mixture of Li , Na , K , Mg ,

Ca , Zn , and Ba was achieved. These separation properties

support that 3a could eﬀectively discriminate ions through

both thermodynamic and kinetic selection mechanisms.

Compared to hosts displaying exclusive ion binding property,

the discrimination ability of 3a is more versatile, allowing

eﬀective ion extraction from a broad range of ion pairs, such as

Rb /Cs (Figure S19 ), Rb /Ba , and Cs /Ba (Figure 2C).

The unique structural features of 3a enable multiple selection

mechanisms operating orthogonally, potentially providing

unparalleled adaptability when functioning in a complex

biological environment.

not observed even if the concentration of Na is 50 times

higher than that of K .

To further explore whether the biomimetic binding tunnel

confers calix[4]trap 3a new discrimination ability, we

investigated the binding properties of 3a to metal ions of

comparable size. Discrete sets of NMR signals were observed

for 3a and 3a·M (M = K , Rb ), suggesting the ion recognition

is slow on the NMR time scale (Figure 2A). Interestingly,

although the binding strength of 3a to K and Rb are quite

similar (Figure 2B), the rate constants for associations (log k )

diﬀer signiﬁcantly, being 3.74, and 2.11 for K , and Rb ,

respectively (Figure 2B). These values reﬂect quite sluggish

associations, which are usually not observed with crown ethers

and cryptands. In an experiment to test the competitive

Given the fact that conformational ﬂuctuation of K

channels has profound inﬂuences on the ion conduction,

3,34

we turned our attention to modify the arene clefts and the

linker to tune the kinetics of ion uptake. Calix[4]traps 3b and

4c were prepared using a similar procedure depicted in Figure

1C. For calix[4]trap 4c, hydrogenation was performed because

a mixture of E and Z stereoisomers were aﬀorded during the

RCM (Figure 3A). Although the introduced substituents are

distal to the tunnel mouth, their inﬂuences on the aﬃnity and

the ion association rates are signiﬁcant (Figure 3B, C).

Compared with 3a, etheric oxygens of 3b and 4c adopt

arrangements unfavorable for ligating metal ions, which may

result in higher organizational demands and lower aﬃnity

(Figure S42). The diﬀerent ion uptake rates could be

attributed to substitution-induced conformational adjustment,

which alters the conﬁned internal environments and portals of

calix[4]traps. As depicted in Figure S41, the incorporation of

substituents has a signiﬁcant inﬂuence on the distance between

the aromatic sidewalls around the crown-ether moiety. As the

distance between the sidewall becomes longer, a drop in the

binding of K and Rb to 3a, a solution of 3a was added to a

cool acetone solution containing K (2.0 equiv) and Rb (2.0

equiv) at −78 °C. When the NMR analysis was performed

immediately after the mixture was warmed to rt, 3a·K was

formed exclusively (Figure S17). Over time at room temper-

ature, the replacement of bound K by Rb occurs but at a very

low rate. In line with our initial design, 3a behaves like a

biomimetic selective ﬁlter, enabling size-dependent ion uptake.

Notably, the kinetically diﬀered ion recognition allows 3a to

eﬀectively discriminate K from Rb , a property that is not

possessed by the original host 1. Given the fact that optimal

K /Na selectivity is usually accompanied by an inferior K /

Rb selectivity (e.g., K /Rb ∼ 1 for KcsA), our strategy

provides a unique solution to address this dilemma. As a step

to further examining the selectivity of 3a toward diﬀerent ions,

H NMR spectra were recorded for mixtures of 3a and a series

of alkaline-earth metal ions, including Mg , Ca , Sr , and

Ba . Surprisingly, none of these ions show appreciable binding

aﬃnities to 3a (Figure S7), which is in sharp contrast to the

aﬃnity to K was observed, probably due to the weakened

K −π interaction. To test whether the distinct ﬂexibility of the

alkyl and alkenyl linkage has a pronounced inﬂuence on the ion

binding, we prepared calix[4]trap 4a via hydrogenation of 3a.

The investigation showed that the recognition properties of

30,31

chelating properties of crown ethers and cryptands.

The

negligible aﬃnity of 3a to alkaline-earth metal ions can be

ascribed to its conﬁned tunnel-like structure, wherein the metal

ions have to be stripped oﬀ their counterions to be swallowed

into the buried cavity, an energetically unfavorable process,

especially for divalent metal ions. In line with this

assumption, the receptor 2a, the precursor of 3a without

calix[4]trap 4a toward K , Rb , and Cs are similar to those of

3a (Figure 4B and Table S15 ), which indicates that the

hydrogenation of the alkenyl linkage only has a minimal

inﬂuence on the ion recognition properties of calix[4]traps.

Unlike most ion hosts that bind ion rapidly by a diﬀusion-

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2,13

Article

controlled kinetics,

calix[4]traps showed a linear relation-

ship between ion radius and association rate, with the slowest

ion capture observed in the formation of 3b·Cs . Besides, all

ion-complexed calix[4]traps display considerable kinetic

stability and retarded ion release. The observed half-lives for

dissociation of K and Rb from the calix[4]traps span over a

range from hours to several days (Table S2). Collectively, the

conﬁned tunnel-like structure result in retarded ion uptake and

release, allowing the recognition kinetics to be ﬁnely tuned.

The tunnel mouth of biological ion channels plays a crucial

role in the initial ion desolvation, which promotes selective ion

transport. However, the ion translocation within a conﬁned

molecular tunnel was rarely experimentally characterized.

Because of the slow uptake of Cs with calix[4]trap 3b, we

were fortunate to observe shifts of 3b′s NMR resonances

before the inclusion of Cs into the buried cavity. Upon the

addition of varying amounts of Cs , the chemical shift of the

resonance H changes gradually (Figure 4B), indicating that

the ﬁrst step of Cs uptake is fast on the NMR time scale.

Pronounced NMR shifts were observed in the methoxy groups

along with the nearby aromatic protons, whereas the H signals

of the buried crown-5 are minimally perturbed (Figure 4A).

These observations can be rationalized by an association within

the tunnel mouth (Figure 4B). As evidenced by the shift of H

signals of methylene bridges, subtle conformational change was

induced upon ion recognition. Over time, NMR shows that

Cs slowly squeezes in the tunnel and enters into the buried

cavity. Base on the H NMR titration experiments, the aﬃnity

of 3b’s tunnel mouth with Cs was determined to be 126.5.

Furthermore, the uptake rate and association constant for the

Figure 3. Kinetic and thermodynamic data for the association

between K , Rb , and Cs and various ion hosts. (A) Chemical and X-

ray single-crystal structures of calix[4]traps 3b and 4c. (B) Measured

logK for complexation of various metal cations with calix[4]traps 3a,

−

3.68

second step of the ion uptake were calculated to be 1 × 10

−

2.41

and 1 × 10 , respectively (for details, see page S44 in the

b, 4a, and 4c in d -acetone/CDCl = 4:1 (v/v) at 25 °C. (C)

Supporting Information). We found that the uptake of Cs into

the deep cavity of 3b is quite slow. When the concentration of

3b (2.9 mM) was mixed with CsSO C F (2.3 equiv), 83 and

Measured log k_i_nfor complexation of various metal cations with

calix[4]traps 3a, 3b, 4a, and 4c in d -acetone/CDCl = 4:1 (v/v) at 25

4 9

°C.

7% of 3b was converted into 3b·Cs after 7.3 and 45 h,

respectively. Notably, the ion uptake rate is found to be

dependent on the anion. When CF CO is used as the

−

Figure 4. Investigation of the ion recognition pathway. (A) H NMR titration of calix[4]trap 3b with Cs before the inclusion of Cs into the

buried cavity. (B) Proposed ion recognition path for the uptake of Cs with calix[4]trap 3b. For detailed assignments, see Figures S26.

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Article

−

counterion instead of C F SO , the rate for Cs to get into

Authors

Zhenchuang Xu − Key Laboratory of Organoﬂuorine

the deep cavity becomes slightly slower (Figure S25 ), probably

because of the better coordinating property of CF CO . The

−

Chemistry, Center for Excellence in Molecular Synthesis,

Shanghai Institute of Organic Chemistry, University of

Chinese Academy of Sciences, Chinese Academy of Sciences,

Shanghai 200032, China

same binding pathway is also adapted by Rb and K , as

deduced by NMR experiments at lower temperatures (Figures

S28 and 29 ). Therefore, the tunnel mouth serves as a

gatekeeper in this sequential dual recognition system, which

senses the ion before uptake (Figure 4B). This interesting

behavior is reminiscent of the gated ion transport in

Nie Fang − Key Laboratory of Organoﬂuorine Chemistry,

Center for Excellence in Molecular Synthesis, Shanghai

Institute of Organic Chemistry, University of Chinese

Academy of Sciences, Chinese Academy of Sciences, Shanghai

biosystems.

00032, China

CONCLUSION

By mimicking the preorganized binding sites of valinomycin

and the consecutive ligating sites of K channels, we

■

Complete contact information is available at:

synthesized a series of novel ion hosts, which simultaneously

possess a deeply buried binding cavity and a conﬁned ion

translocation tunnel. Mechanistic studies verify that the host’s

portal could discriminate metal cations by their size, enabling

varied ion uptake rates. The conﬁned tunnel bearing

consecutive binding sites promotes complete desolvation of

ions during their inclusion into the buried cavity, mimicking

the ion translocation within biological ion channels. The

merging of selection strategies learned from valinomycin and

Notes

The authors declare the following competing ﬁnancial

interest(s): The authors have ﬁled a patent on this technology.

ACKNOWLEDGMENTS

■

This research was supported by the National Natural Science

Foundation of China (21871291, 91956120, 21421002). The

authors thank Ms. Xian Cai, Prof. Xin Zhao, and Ms. Shuyan

Jiang for their kind help in thermodynamic and kinetic study,

and Ms. Lijun Zhang for the ICP-MS test. We also thank Ms.

Suzhen Zhu for painting the nepenthes. Y.Z. thanks Fang

Wang for the critical reading of the manuscript.

K channels proved useful to further boost the record-setting

selectivity and make possible the modulation of successive

recognition events evolving in space and time. The capability

to manipulate guest recognition both in equilibrium and out-

of-equilibrium states allows the host to eﬀectively discriminate

diverse guests via distinct mechanisms. The strategy to merge

orthogonal selection mechanisms into a single host oﬀers new

opportunities to create more robust supramolecules and

functional materials that may function in complex biological

environments.

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