Construction of a Switchable Nanochannel for Protein Transport via a

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Construction of Switchable Nanochannel for Protein Transport via Pillar[5]arene based Host-Guest System Fan Zhang, Junkai Ma, Yue Sun, Yuxiao Mei, Xue Chen, Wenqian Wang, and Haibing Li Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.8b01948 • Publication Date (Web): 07 Jun 2018 Downloaded from http://pubs.acs.org on June 7, 2018

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Analytical Chemistry

Construction of Switchable Nanochannel for Protein Transport via Pillar[5]arene based Host-Guest System Fan Zhang, Junkai Ma, Yue Sun, Yuxiao Mei, Xue Chen, Wenqian Wang, and Haibing Li* Key Laboratory of Pesticide and Chemical Biology (CCNU), Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, P. R. China ABSTRACT: Modulating protein selective translocation is a significant process, which has great potential for mimicking and understanding complex biological activities. As such, how to construct a nanochannel that can well gating protein transport is vital and challenge. Herein, inspired by nature, we presented a robust strategy to construct a switchable nanochannel by introducing a pH responsible binary host-guest system into nanochannel. Benefit from the novel design of the pillar[5]arene as gatekeeper, the functional nanochannel can well facilitate histone transport. Under pH regulation, the host-guest assembled nanochannel is capable of switching “on” and “off” to manipulate histone translocation process. This study exemplifies the importance of molecular switch mediated protein transport in this process, and provides a new theoretical model for biological research, which will open a new avenue for better understanding of some physiological and pathological behaviors.

Protein transport in confined channel is a significant process. For example, histone transport across the nuclear pore complexes (NPCs) plays vital roles in nucleocytoplasmic exchange and signal transmission.1-3 In fact, NPCs can only work in the biological environment of nuclear envelope, which impedes the application of NPCs for practical study in vitro. As such, development of robust artificial system to mimic the gating behaviors of protein selective translocation is of profound significance.4-8 Inspired by biological channel, artificial smart nanochannel architectures were rapidly developed and boosted the applications of nanochannel in many areas, such as nanofluidic devices, biochemical sensing, filtration and energy conversion. Among the various artificial nanochannels, solid state synthetic nanochannels have attracted extensive attention due to their intrinsic advantages including flexible geometry and size, excellent mechanical properties and easy to functionalities on the surface. For these reasons, a great number of versatile nanochannels have been developed in recent years by anchoring ambitious functional receptors into nanochannel systems. Some of these smart nanochannel systems can serve as special gate to modulate protein selective translocation.9-17 However, nanochannel immobilized with antibody or aptamer could lead to irreversible binding for the protein and receptor, and resulting in the blocking of the nanochanel. In this context, a flexible gate that can mediate the channel open and close reversibly is vital and crucial for protein transport, which is at present largely unexplored and of great challenge. Therefore, how to construct a switchable nanochannel that can precisely regulated protein transport is highly anticipated. Binary supramolecular host-guest architectures with reversible binding and releasing properties are promising candi-

dates for constructing molecular switch. And studies have also proved that supramolecular ligands can serve as good receptors for modulating and capturing biomolecules, such as amino acids, peptides and proteins.18-22 Therefore, harnessing these properties, the idea to fabricate a tunable protein gate was proposed by introducing of a binary supramolecular system into nanochannel. Pillar[5]arenes, as a new generation of supramolecular host, have gained enormous attentions in recent years owing to their outstanding ability of host-guest based supramolecular switches, such as pseudorotaxanes, rotaxanes, catenanes, supramolecular dimers, etc.23-25 These superior features endow them versatile applications in molecular gating devices, sensing and filtration.26-30 Taking these into account, we proposed a new strategy for switchable nanochannel guarding protein transport through embedding the pillar[5]arene based binary host-guest system into nanochannel. Herein, the design and construction of a switchable nanochannel for protein transport were elaborated in Scheme 1. In this work, we introduced a pillar[5]arene based host-guest system into nanochannel to construct a switchable nanochannel modulated histone transport. In the absence of host molecule, the nanochannel performed “off” state that impeded protein transport. While activated by the host pillar[5]arene, the nanochanel showed a “on” state that effectively regulates protein transport based on the molecular recognition motif. In addition, the pillar[5]arene in this intelligent system can be bound and released in response to different pH condition, which can be utilized as a switchable gate for precisely regulation of protein transport.

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Scheme 1. Design of a binary host-guest gated nanochannel for protein transport inspired from biological nucleopore.

EXPERIMENTAL SECTION Materials and Reagents. Poly (ethylene terephthalate) (PET, 12 µm thick) membranes were irradiated with single heavy ion (Au) of energy 11.4 MeV/nucleon at UNILAC linear accelerator (GSI, Darmatadt, Germany). 1-Ethyl-3-(3dimethyllaminopropyl) carbodiimide hydrochloride (EDC •HCl,≥98.5%), N-hydroxysulfosuccinimide (NHS, ≥98.0%), 1,6-hexanediamine (HDA), formic acid (HCOOH), sodium hydroxide (NaOH), hydrochloric acid (HCl), potassium chloride (KCl), sodium hydrogen phosphate (Na2HPO4 •12H2O), sodium dihydrogen phosphate (NaH2PO4) were purchased from Sinopharm Chemical Reagent Shanghai Co., Ltd. (SCRC, China). Histone H3 (calf thymus, 15.3 KDa), Lysozyme (14 KDa), Ovalbumin (44.5k Da) and N-Acetyl-L-Cysteine (NAC) were purchased from Sigma-Aldrich. All chemical reagents were all used as received, electrolyte solution were prepared in MilliQ water (18.2 MΩ). Current-voltage curves were measured by a Keithley 6487 picoammeter (Keithley Instruments, Cleveland, OH). Confocal fluorescent images were acquired using a Zeiss confocal laser scanning unit mounted on a LSM710 fixed-stage upright microscope. UV-vis absorption spectra were recorded on UV-2501. 1

H NMR spectra test. 1H NMR spectra (D2O, 298 K, 600

MHz) were recorded on Varian Mercury Plus 600 spectrometer with TMS as the internal standard. The pH regulation experiments were conducted by addition of DCl and NaDH in the solution.

Nanochannel fabrication. Single conical nanochannel was prepared using an asymmetric track-etch technique on a 12 µm thick PET membrane (Hostaphan RN12 Hoechst) with a single heavy-ion-irradiated track in the center. Before the chemical etching process, both side of the PET membrane was exposed to UV light (365 nm) for1 hour. In order to obtain the conical nanochannel, etching solution (9 M NaOH) was filled in only from one side of chamber, the other side of the cell contains a solution (1 M HCOOH +1 M KCl) that is able to neutralize the etchant as soon as the pore opens, thus slowing down the further etching process. Then a voltage of 1 V was applied across the membrane (Figurs S6). The etching process was stopped at a desired current value corresponding to a cer-

tain tip diameter. The membrane was immerged in MilliQ water (18.2 MΩ) to remove residual salts.

Chemical Modification. After chemical etching, carboxyl groups are generated on the nanochannel surface. Thus the film can be activated with EDC/NHSS, forming an aminereactive ester intermediate. Then these reactive esters were further condensed with HDA through the formation of covalent bonds. In this paper NHSS ester was formed by soaking PET film in 4 mL aqueous solution of 30 mg EDC and 6 mg NHSS for 1 hour. After that washing this film with distilled water and treated it with 5 mM HDA solution overnight. Then, the film was soaked in 1 mM water-soluble N-AcetylCysteine-pillar[5]arene (ACP5) for self-assembling. Finally, the modified film was washed three times with distilled water. SEM Measurement. Scanning electron microscopy (SEM) measurements were captured in the field-emission mode using a Hitachi S-4800 microscope at an acceleration voltage of 5 kV. X-ray photoelectron spectra experiment. X-ray photoelectron spectra (XPS) data were obtained with an ESCALab220i-XL electron spectrometer from VG Scientific using 300 W Al Kα radiation. All peaks were referenced to C1s (CHx) at 284.8 eV in the deconvoluted high resolution spectra. Ionic current measurement. Ion currents were measured by a Keithley 6487 picoammeter (Keithley Instruments, Cleveland, OH). Ag/AgCl electrodes were used to apply a transmembrane potential across the film. The film was mounted between the two halves of the conductance cell. Both halves of the cell were filled with a 0.1M KCl, pH 7.23. In order to record the I–V curves, a scanning triangle voltage signal from -2V to +2V with a 40s period was selected. Each test was repeated 5 times to obtain the average current value at different voltage. All of the experiments were carried out at room temperature (25 ℃). Protein translocation test. A Dagan cornerstone chemclamp amplifier connected to a computer through a field programmable gate array data acquisition card (FPGA card, PCIe7852R, National Instruments) was used to apply the desired transmembrane potentials and measure the resulting ion current flowing through the electrolyte-filled nanopore between two Ag/AgCl electrodes. The current was recorded in the voltage-clamp mode with a low-pass Bessel filter at 3 kHz band-


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width. The measurement of histone translocation was conducted in two isolated containers that mounted with a single conical nanochannel PET film in the central (Figure S6). Both cell filled with electrolyte 0.1 M KCl +0.01M PBS (pH = 7.23), and 1µM histone added in the tip side, the transmembrane potential + 2V was held to drive the positive charged histone to pass through the nanochannel from the tip to base.

RESULTS AND DISCUSSION Design of host-guest system. The reversibility and selectivity are the two essential criteria for designing a switchable nanochannel. Thus, given that histone rich of cationic side chains of arginine and lysine residues, we designed a negative charged host N-acetyl-cysteine pillar[5]arene (ACP5) that serve as the histone receptor. In this vein, 1,6-hexanediamine (HDA) was selected as a guest molecule for interaction with host. Initially, the synthesis of water-soluble ACP5 was using a high efficient and rapid photocatalytic “thiol-ene” click reaction according to our previous work.31, 32As shown in Scheme S1, the obtained ACP5 was characterized by using 1H NMR and 13C NMR spectroscopy, MALDI-TOF MS (Figure S13S16 in Supporting Information). As we expected, the ACP5 host molecule was successfully obtained. Subsequently, details of the interaction of HDA and ACP5 were measured through 1 H NMR titration experiment. With the added HDA increasing, the proton peak on benzene of ACP5 gradually downshifted (Figure S1). The mole ratio plots based on the proton NMR data showed that the complexes of ACP5 and HDA had a 1:1 stoichiometry in water at room temperature (Figure S2 in Supporting Information). These results revealed that ACP5 and HDA can form a host–guest complex driven by hydrophobic interactions. It is well known that neutral carboxylic acid and anionic carboxylate can be converted reversibly by adjusting the solution pH. Thus, on the basis of the anionic carboxylate groups of ACP5, the dethreading and rethreading process of the complex ACP5-HDA can be controlled by the pH changes. As shown in Figure S3, the ability of pH regulating the host-guest interaction was verified by 1H NMR experiment. Delightedly, when adding with an aqueous DCl into the ACP5-HDA solution, the signals for all protons on the ACP5 disappeared immediately and the chemical shift changes of guest returned to their original positions just as free HDA. This result may attribute to the anionic carboxylate groups on ACP5 were protonated, and then the water-soluble ACP5 precipitated from the solution associated with the disassembly of the host-guest inclusion complex. After the addition of NaOD into the system (Figure S3c), the insoluble carboxylic acid groups would be deprotonated. Thereby, the ACP5 host would become soluble in water again, simultaneously form host-guest complex with HDA. The results evidently confirmed that the binding and releasing processes of the ACP5-HDA complex can be easily controlled by changing the solution pH. Selective interaction of ACP5 and proteins. In order to demonstrate the selective interaction of ACP5 and histone, the isothermal titration calorimetry (ITC) characterizations were conducted to investigate the binding behaviors between ACP5 and different proteins (ovalbumin, lysozyme, histone). As shown in Figure S4, the results indicated that the ∆H is -11580

± 154 cal/mol when ACP5 interacted with histone, while for the interaction with ovalbumin and lysozyme, the ∆H difference were -32.83 ± 21 cal/mol and -1406 ± 279 cal/mol, respectively. Therefore, the results corroborated ACP5 has higher binding affinity towards histone. Additionally, to further confirm the selective interaction of ACP5 and histone, zeta potential test was carried out. As shown in Figure S5, with the addition of different concentrations (as high to 1.2 µM) of ACP5 into various proteins (1.0 µM, 0.03M PBS, PH = 7.23), only histone led to potential change with charge decreased. This may be attributed to the cavity of negative charged ACP5 inclusion the residue of histone, which leads to charge decrease. Therefore, all these results vividly demonstrated that ACP5 can serve as affinitive receptors to interact with histone. Construction of binary host-guest assembled nanochannel. Motivated by the above properties of host-guest motif in solution, we attempted to fabricate a switchable nanochannel with the idea of the introducing pH modulated supramolecular selfassembly system into nanochannel. At first, single conical nanochannel was prepared using an asymmetric track-etch technique, and the morphology was analyzed and characterized by scanning electron microscopy (SEM). The image of cross section in Figure 1 vividly proved that conical nanochannel was successfully prepared, and the large opening (base) was measured about 860 nm in diameter, while the tip diameter was around 28 nm.

Figure 1 The SEM images for the conical nanochannel. (a) The cross section of prepared nanochannel. (b) The diameter of base side and (c) the tip side.

After the chemical etching process, carboxyl groups were exposed on the nanochannel surface, and then HDA covalently linked to the -COO- groups by a classical EDC/NHSS crosslinking reaction. Subsequently, ACP5 anchored on the nanochannel surface through self-assemble process (Figure 2a). After well prepared, the successful modification of the nanochannel was verified by the corresponding current–voltage (I-V) curves. As shown in Figure 2b, the original nanochannel tested in 0.1 M KCl + 0.01M PBS (pH 7.23) electrolyte showed a nonlinear I–V curve with the current -10.02 nA at 2V, gave a rectification ratio of 32.9. After modified with HDA, the rectified current dramatically decreased to -0.76 nA, and the rectification ratio dropped to 10.8. This can be attributed to the decrease of negative charge on the nanochannel surface. Afterward, anchoring rich negative charged ACP5 on the nanochannel surface led to a 4.6-fold current increase on the base of HDA-immobilized nanochannel. The current



sharply increased to -4.24 nA at -2V, and the rectification turned into 18.6. These changes in the I–V curve demonstrated the nanochannel has been successful fabricated. To further verify the modification of naochannel, contact angles (CA), Xray photoelectron spectroscopy (XPS) and laser scanning confocal microscopy (LSCM) analyses were carried out. As shown in Figure S7, the CA of the etched membrane with unreacted -COO– was 61.5 ± 0.4°, and the HDA modified on the surface of the film, it appeared to be hydrophobic with a CA of 77.1 ± 0.8°. Assembled with ACP5, it showed a significantly hydrophilic surface with a CA of 58.6± 1.3°. In addition, the wide energy spectrum of XPS showed that N1s peak at 399.62 eV is appeared in the HDA modified membrane, and the S2p peak is observed at 163.43eV after completing the ACP5 assembly process (Figure S9). The LSCM analysis showed that after the rhodamine B amine (RhB–NH2) labeled ACP5 assembled on the nanochannel, a fluorescence signal was observed in a thickness of ca. 13.0 ± 0.5 µm, which agreed with the actual thickness of the PET membrane (Figure S10). In order to illustrate the stability of host-guest assembled nanochannel, a repetitive current was measured with a scanning voltage varying from −2 V to +2 V. As shown in Figure S11, as the time change, no obvious ion conductance change was observed. Hence, all these characterization data illustrated that the host-guest assembled nanochannel was successfully constructed, and the host-guest system possesses excellent stability.

Switchable properties of the host-guest assembled nanochannel. The host-guest assembled nanochannel is of prime importance for its non-covalent interaction, which endows the system with switchable properties and reversibility. To investigate the pH response of this binary host-guest functionalized nanochannel, we recorded the ion currents after treated with different pH conditions. As shown in Figure 3, when the HDA-immobilized nanochannel assembled with ACP5 in neutral condition, the current recorded at -2V was around -4.2 nA, which showed ON-state with high current. Thereafter, the nanochannl was treated with a solution at pH = 4.5 for ten minutes, and tested the current in neutral condition, the nanochannel turned to the OFF-state, with low current of -0.78 nA. The current appeared consistent with the nanochannel in HDA-modified step. Then, the current of nanochanel was tested in neutral solution with a fixed voltage of -2V, and the nanochannel returned to the ON-state with a current around -4.2 ± 0.2 nA. Alternating treatment with solution of pH = 4.5 and addition of ACP5, the ionic current can reversibly switch between -4.2 nA and -0.78 nA with several cycles, which indicates that pH can well switch the host-guest assembled nanochannel with excellent reversibility and stability. Moreover, to further illustrate the pH mediated switch behavior of the host-guest assembled naochannel, contact angles (CA) test were also performed to explore the reversible properties under the same conditions. As shown in Figure S8, the ACP5 attached film surface shows a significantly hydrophilic surface with a CA of 58.6± 1.3°. Upon treatment with pH=4.5 solution and washing with deionized water, the CA returned to that of the HDA-modified with a CA of 77.6 ± 1.2°. Repeating the process, the CA wettability results can well switch for five times, indicating the good reversible change of pH regulated the surface properties.

Figure 3. Stability and responsive switching ability of the pH regulated host-guest naochannel. The experiments were conducted in 0.1M KCl +0.01M PBS (pH 7.23).

Figure 2 Fabrication of host-guest assembled nanochanel. (a) The structure of host ACP5 and guest HDA. (b) I-V curves for the modification process with the electrolyte 0.1M KCl +0.01M PBS (pH 7.23). (c) Rectification ratio change for each step. The result showed that ACP5 assembled nanochannel was successfully prepared.

Protein transport in host-guest nanochannel. The success of constructing the binary host-guest functionalized nanochannel inspired us to further use the switchable system to modulate protein transport. A positive charged histone was utilized as the analyte molecule. The process of protein selective transport in biomimetic nanochannel was monitored by chemclamp technology. First, control experiments were performed without adding of histone for the HDA and ACP5 modified nanochannel. As shown in Figure 4, in the absence of histone, it resulted in a steady-state ion current of 1.2 nA and 4.6 nA


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for the nanochannel, which was free of transient current-block events. When free protein molecules entered into the single functional nanochannel, the ionic current showed an obvious resistive-pulse signature. These individual translocation events resulted in a series of clear pulses in the current trace. But for the HDA modified nanochannel, addition of the 1 µM histone to the solution generated bits of transient current-block events, which represented “off” state for histone transport (Figure 4a). While for the ACP5 host assembled nanochannel, the histone molecules were expected to translocate through the nanochannel by electrophoresis and electroosmosis and numerous transient current-block events were observed, which represented “on” state for histone transport. The results clearly demonstrated that ACP5 showed higher affinity for histone, thus can act as a good receptor for facilitating histone transport. Figure 5. The event frequency of protein transport in the hostguest gated nanochannel.

CONCLUSIONS

Figure 4. Time dependence of current change for 1 µM histone transport in guest (a) and host molecule (b) modified single nanochannel. The concentration of the histone is 1µM. The electrolyte 0.1M KCl+0.01M PBS (pH =7.23), with the transmembrane potential held at +2V (anode on the tip side).

A comparison of the histone translocation event rates was calculated in Figure 5. Notably, the histone transport in HDA channel yielding frequency 0.12 events/s, while with frequency 1.1 events/s for the ACP5 assembled channel, which indicated the host-guest assembled nanochannel can well facilitate histone transport. Subsequently, to investigate the switchable properties of the host-guest gated nanochannel controlling protein transport, we tested the histone transport properties of the nanochannel after repeat alternately treated with pH 4.5 solution and ACP5 solution. The results shows a reversible and highly robust “off” and “on” switching for protein translocation process, thus indicating the host-guest assembled nanochannel has excellent stability and reversibility to precisely manipulate histone transport. The reproducibility of the proposed method was evaluated by count statistics for different times from the same prepared membranes and the standard error was about 4.18% (Figure S12). These results vividly proved the advantage of the host serve as receptor, and selectively controlling the histone transport based on the molecular recognition.

In summary, a biomimetic switchable nanochannel was successfully developed by immobilizing ACP5 based host-guest system onto nanochannel. The binary supramolecular motifs possessed a reversible “on-off” switching ability and stability by virtue of the unique pH manipulated host-guest interaction, and endowed abundant flexibility to mediate protein transport. The results suggested that ACP5 assembled nanochannel has good selectivity for histone, which facilitated the protein enter into nanochannel and dominated the process of protein translocation. These findings firmly demonstrated the ACP5 can act as protein receptors and propose a general design principle of molecular recognition-induced protein transport, which sheds light to the role of ligand selectivity in nanopore gated protein transport process. Given these promising results, we appreciated that the system will open a new avenue for better understanding of some complex biological processes, and this technology can broad many applications, such as intelligent controlling of drug delivery, analysis of biomolecules and gene therapy.

ASSOCIATED CONTENT Supporting Information. More details for the 1H NMR, 13C NMR and MALDI-TOF for the N-acetyl-cysteine -pillar[5]arene (ACP5). 1H NMR for pH regulated host-guest interaction. Isothermal titration calorimetry (ITC) characterization, Zeta potential characterization, Contact angles measurement, XPS analysis for before and after modification, current-pulse analysis. This material is available free of charge via the internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Author * [email protected]

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT This work was financially supported by the National Natural Science Foundation of China (21572076, 21372092), the 111 Project (B17019) and Self-determined research funds of CCNU from the colleges’ basic research and operation of MOE.



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Analytical Chemistry For TOC Only

In this work, we presented a binary host-guest gated nanochannel that can be switched “off” and “on” to manipulate proteins transport. Benefit from the unique design of the pillar[5]arene as gatekeeper, the host assembled nanochannel is capable of regulating histone transport with high selectivity. This study exemplifies the importance of molecular switch mediated protein transport in this process, and provides a new theoretical model for biological research, which will open a new avenue for a better understanding of some physiological and pathological behaviors.


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Construction of a Switchable Nanochannel for Protein Transport via a

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