Organic Nanotube with Subnanometer, pH-Responsive Lumen

Article abstract of DOI:10.1021/jacs.9b03732

While many synthetic nanotubes with a hydrophobic lumen and fast molecular transport have been developed, decorating the interior of these channels with polar and/or responsive functional groups remains challenging. In transmembrane proteins like the aqua

Full text of DOI:10.1021/jacs.9b03732

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Organic Nanotube with Subnanometer, pH-Responsive Lumen
Shawn M. Darnall, Changyi Li, Martha Dunbar, Marco A. Alsina, Sinan Keten, Brett A. Helms, and Ting Xu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b03732 • Publication Date (Web): 25 Jun 2019
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Organic Nanotube with Subnanometer, pH-Responsive Lumen
Shawn M. Darnall,† Changyi Li,‡ Martha Dunbar,¶ Marco Alsina,¶ Sinan Keten,¶ Brett A.
Helms,∗,‡ and Ting Xu∗,‡,†,§
†Department of Materials Science & Engineering, University of California, Berkeley, Berkeley, CA 94720,
USA
‡The Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA
¶Department of Civil & Environmental Engineering and Mechanical Engineering, Northwestern University,
Evanston, Illinois 60208, USA
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§Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA
Received June 6, 2019; E-mail: bahelms@lbl.gov; tingxu@berkeley.edu
number or type of the amino acids in the CP backbone,
and recent efforts have focused on introducing new chemical
Abstract: While many synthetic nanotubes with a hydrophobic
lumen and fast molecular transport have been developed, dec-
orating the interior of these channels with polar and/or respon-
sive functional groups remains challenging. In transmembrane
functionality to the interior.24 Hydrophobic features includ-
ing a methyl group20 and portions of cyclic rings have been
introduced to the interior by using artificial amino acids.25,26
Introducing different polar or stimuli-responsive groups
to the interior of the CPN is much more desirable to mimic
natural channel proteins, but success is rather limited. The
earliest example relied on a lipid environment to twist exte-
rior polar groups into the interior.27 Later, cyclic γ-residues
were used to insert hydroxyl28–30 and hemiaminalic oxy-
gen31 functionalities. The hydroxyl group, however, inter-
acted with the backbone and limited assembly to spherical
clusters rather than forming straight nanotubes which are
preferred for separations. CPNs with fluorinated interiors
were recently reported.32 Considering the design of these dif-
ferent CPNs, in particular to maintain subnanometer chan-
nel diameters needed for size selection, there are many chal-
lenges to making CPNs with polar interiors. The main ob-
stacles include eliminating unintended hydrogen bonds that
prevent nanotube formation,29 reducing side reactions, and
cyclizing peptides with bulky protecting groups.
proteins like the aquaporin and M2 channels, the presence of
histidine residues in a mostly hydrophobic channel has led to en-
hanced selectivity and pH-based activation. Herein, we report
the synthesis of Bzim-CP, a cyclic octapeptide that contains a
benzimidazole functionality as a chemical and structural mimic
of histidine. Bzim-CP undergoes different protonation states,
forms sub-nanometer nanotubes, and projects two different ion-
izable functionalities into the lumen. Present studies open up
synthetic possibilities to functionalize sub-nm porous channels
as basis toward understanding new transport phenomena.
Nanotubes are promising materials capable of fast separa-
tions with molecular sieving,1–3 but obtaining enhanced sep-
aration properties relies on controlling their pore dimensions,
size-dispersity, and interior chemical functionality.2 Trans-
membrane proteins such as aquaporin4 and the M2 channel5
have well-defined channel interiors that include polar amino
acids like histidine in a hydrophobic channel. These fea-
tures enable exceptional selectivity, flux, and even stimuli-
responsive behavior for the M2 channel and have inspired
the design of many synthetic nanochannels.
Herein, we report a CPN that contains a benzimidazole
group in the backbone where each sub-unit projects one of
two ionizable nitrogen groups to the interior. The struc-
tural and chemical similarity to histidine’s imidazole group
introduces pH-responsive properties to the CP.
Fully mimicking these structural and chemical properties
synthetically has been nontrivial if not impossible. Carbon
nanotubes6–9 and pillarenes10 have fast water transport due
to confinement and their hydrophobic and smooth interior,
but they are difficult to functionalize internally and con-
trol for size. Lyotropic liquid crystals self-assemble into
three dimensional structures with interconnected, highly
charged pores that separate molecules by polarity, charge,
and size.11,12 Although they have been macroscopically fab-
ricated into desalination membranes, processing limitations
and lack of a hydrophobic core limit water flux. Metal or-
ganic frameworks have pores with tunable chemistry and
geometry that are promising for separations.1,13 However,
they can be difficult to incorporate into polymeric mem-
branes because of materials compatibility issues.14
Synthesis of the benzimidazole-containing CPN, Bzim-
CP, is shown in Scheme 1 and started with synthesizing
an artificial amino acid. To eliminate side reactions dur-
ing the subsequent step, 1 was esterified and recrystallized
in ethanol to produce 2 (62%). Boc protection of the aniline
was performed using di-tert-butyl-dicarbonate and DMAP
in toluene producing 3 (74%). The ester was subsequently
hydrolyzed using NaOH in a water/ethanol mixture. After
careful acidification, extraction, and recrystallization, 4 was
obtained (68%). The nitro group was fully hydrogenated
using H2 and 5% Pd/C in methanol, affording 5 and used
without further purification. Fmoc-protection of the aniline
group was attempted using Fmoc-Cl and Fmoc-OSu but had
low yield due to side reactions. Instead, protected dipeptide
6 was formed by synthesizing Fmoc-d-Ala-Cl and reacting
it with 5 (61%).
Self-assembling cyclic peptides (CP) can form high aspect
ratio nanotubes (CPN) with subnanometer channels. They
can mimic the hourglass shape of transmembrane channels15
or be used to generate porous membranes with oriented
channels.16,17 Pore size,18,19 shape,20 and exterior chemi-
cal properties21–23 can be precisely tuned by changing the
Using SPPS on a 2-chlorotrityl chloride resin, linear pep-
tide chain, H2N-6-A-K-A-L-A-K-OH, was grown. (Under-
line denotes d-stereoisomer). The placement of dipeptide 6
in the sequence is important for CP cyclization and was sys-
tematically screened. The optimal location was at the end of
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the growing chain. Placing it earlier also resulted in either
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premature cleavage from the resin or side reactions. The
protected peptide was released from the resin using 1% tri-
fluoroacetic acid (TFA) in DCM and cyclized using HATU.
Other coupling agents (T3P, DIC/HOBt, HCTU, HBTU,
PyBOP) were tested but had negligible yield. A final depro-
tection in TFA at 60◦C resulted in a ring-closing reaction
between 5 and the neighboring carbonyl, producing Bzim-
CP. The product was purified by HPLC and characterized
by LC-MS and NMR (SI3.1-3.4). NMR spectra indicate that
both the exterior and interior nitrogens of the benzimidazole
are bonded to hydrogen in equal likelihood (SI3.3).
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Scheme 1. Synthesis of Bzim-CP
Figure 1. a) FT-IR spectra of dried Bzim-CP nanotubes. b)
Circular dichroism spectra of Bzim-CP in 10 mM tris buffer, pH
7.4 and organic solvents. MeCN samples were taken as a suspen-
sion. c) Temperature dependence of Bzim-CP and the two CPN
variants shown in (d).
CP differed greatly despite both containing aromatic com-
pounds, with Mba-CP lacking β-sheet signatures. Each so-
lution was also heated from 20◦C to 65◦C, and the over-
all curve shapes were maintained, indicating thermal sta-
bility of the CPNs. The peaks for (KA)4-CP and Mba-CP
showed a 14% and 21% decrease, respectively, in intensity
while Bzim-CP showed an overall upward shift. In acetoni-
trile, (KA)4-CP also did not dissolve, but Mba-CP did at 100
µM and its spectra suggests nanotube formation as reported
previously.20 Considering their relative solubilities and CD
spectra in the different solvents, (KA)4-CP likely has the
greatest ability to form nanotubes, followed by Bzim-CP.
Molecular dynamics simulations were performed to fur-
ther study the in-solution equilibrium assembly behavior of
Bzim-CP nanotubes. Toluene, a low dielectric solvent, was
used to strongly encourage hydrogen bonding between CPs
for nanotube formation, Figure 2 and SI4. Bzim-CP formed
Individual CPs stack to form nanotubes through hydro-
gen bonds, resembling antiparallel β-sheets which can be
measured by spectroscopy.33 Nanotubes were drop-cast onto
a CaF2 plate, and their solid-state assembly behavior was
probed by FTIR, Figure 1a. Bzim-CP strongly absorbed at
3272, 1632, and 1545 cm–1 which correspond to the Amide A
−
(N−H stretching), Amide I (C O stretching, perpendicular
−
component), and Amide II (N−H bending and CN stretch-
ing) bands, respectively, and are indicative of β-sheets34 and
nanotube formation. The spectra is similar to and within a
few cm–1 of other reported CPNs.16,20,33 1673 cm–1 is due
to residual TFA from HPLC purification.35
Circular dichroism (CD) was used to study the assem-
bly in solution, Figure 1b. Bzim-CP readily dissolved in
10 mM tris buffer (pH 7.4), methanol, and ethanol, and
typical β-sheet signatures were measured with a peak and
trough near 200 nm and 220 nm, respectively. This finding
indicates that there is still a significant degree of nanotube
formation despite hydrogen bond competition from the sol-
vent. The slight differences in peak and trough locations
suggest solvent-dependent changes in the CP stacking be-
havior or backbone configuration. Bzim-CP, however, did
not dissolve in acetonitrile even at concentrations down to
1 µM, but a 40 µM suspension did show β-sheet-like signa-
ture with an offset trough. Crystallization of Bzim-CP was
attempted to probe the differences in stacking behavior but
was unsuccessful.
Bzim-CP was compared to two variants, (i) (KA)4-CP17
which contains only α-amino acids and (ii) Mba-CP20 which
uses a γ-amino acid for interior methylation, Figure 1c and
1d. In methanol, the spectra for Bzim-CP had similar peak
and trough wavelengths as that for (KA)4-CP, although in-
tensities varied and suggests different degrees of nanotube
formation. Surprisingly, the spectra for Bzim-CP and Mba-
Figure 2. MD simulations of Bzim-CP assembly in toluene de-
pending on whether N−H is on interior (a,c,e,f) or exterior
(b,d,f,h). a,b) The respective chemical structure. c,d) Dimer for-
mation with hydrogen bond formation between benzimidazoles
highlighted in (c) in pink. e-h) Side and cross-sectional views of
nanotubes.
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fewer inter-ring bonds than (KA)4-CP, which is consistent
was conjugated to the exterior lysine handles. The CPN-
PEG conjugates were cast from dimethylformamide, result-
ing in shorter and narrower individual nanotubes measuring
121 ± 56 nm long and 7 ± 1 nm wide.
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with its weaker CD signal. The ring-stacking behavior was
also found to be dependent on which nitrogen on the benz-
imidazole was protonated. When the lumen contains the hy-
drogen, the N−H group aligns well with the carbonyl on the
neighboring ring, allowing on average 6.4 hydrogen bonds to
form between neighboring CPs, Figure 2c and 2e. Straight
nanotubes are formed, which is ideal for transport. How-
ever, when N−H is located on the exterior of the nanotube,
the same alignment cannot occur, resulting in only 5.3 hy-
drogen bonds forming. To compensate, the CPN bends to
increase inter-ring interactions, Figure 2d and 2f. The side
and cross-sectional views give further insight into the back-
bone configuration and the stacking behavior. The benzimi-
dazole group splays off at an angle instead of lying flat in the
ring. Hydrogen bonding is maximized by stacking the CPs
in an antiparallel fashion, where the benzimidazole group in
adjacent rings angle in the opposite directions.
The change in electronic structure of the Bzim-CP back-
bone was monitored as a function of pH using UV-Vis spec-
troscopy, Figures 4a and 4b. At pH 2.1, an absorbance peak
and shoulder at 250 nm and 280 nm, respectively, were ob-
served. With increasing pH, the absorption peak and shoul-
der shifted to 270 nm and 300 nm, respectively, before be-
coming a single peak at 315 nm, revealing three protona-
tion states with pKa values of approximately 3.2 and 11.5.
Reversing the pH showed that the absorption change is re-
versible. Loss of the β-sheet signal was observed by CD as
the pH was decreased below the lower pKa, Figure 4c. The
normalized signal at 220 nm correlated strongly with the
protonation states predicted by the Hendersen-Hasselbalch
equation, suggesting that the CPN disassembles due to ionic
repulsion from the positively charged benimidazole groups.
Due to high absorbance, this process could not be repeated
near the higher pKa but is expected to be similar as Bzim-
CP becomes negatively charged. (KA)4-CP and Mba-CP
showed no pH dependence under the same conditions be-
cause they have no ionizable backbone groups in this pH
range (SI3.5). While Bzim-CP dissociates in solution at ex-
treme pHs, putting Bzim-CP in a condensed phase like a
polymer matrix may help maintain the structure, and fur-
ther stabilization may be possible by doping in other CPs
into the nanotube to separate charged CPs.38,39 The lat-
ter approach would also better mimic the chemical makeup
found in protein channels.
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To conclude, we have developed an organic nanotube that
introduces new pH-responsive properties into the interior of
the channel, and its polymer conjugate should be amenable
to subnanometer porous film fabrication.17 Because the ben-
zimidazole functionality mimics histidine side chains, Bzim-
CP may introduce new biomimetic transport properties such
as those found in transmembrane channels, and future work
will focus on closely studying how the different interior prop-
Figure 3. AFM of Bzim-CP nanotube bundles cast from (a)
toluene and (b) DMF. (c) TEM of Bzim-CP cast from acetoni-
trile. (d) AFM of PEG-conjugated Bzim-CP cast from DMF. lp
is the measured persistence length.
Dried Bzim-CP nanotubes were visualized as final con-
firmation of assembly, Figure 3. Using atomic force mi-
croscopy, samples spun-cast from toluene were observed as
large, networked bundles of nanotubes. In contrast, Bzim-
CP cast from dimethylformamide formed straight nanotube
bundles measuring 583 ± 390 nm long and 30 ± 7 nm wide.
Bzim-CP in acetonitrile was drop-cast onto a carbon grid
and negatively stained for TEM imaging. Highly curved,
entangled bundles measuring 482 ± 310 nm long and 14 ±
2 nm wide were observed. The various degrees of bundling
between the samples likely resulted from both differences in
the hydrophobic effect in solution as well as a hierarchically-
oriented alignment driven by the local concentrations of nan-
otubes upon drying.36,37 Due to the apparent differences in
curvature, the persistence lengths, lp, were approximated by
comparing contour lengths and end-to-end distances of the
bundles (SI3.8). The lp of samples cast from DMF were 8.4x
longer than those from acetonitrile. Errors associated with
measuring their diameters made comparing bending moduli
difficult, but differences in diameters likely caused the ob-
served differences. For dispersion and future integration into
polymer films, poly(ethylene glycol) (MW = 2000 g/mol)
Figure 4. The changes in (a) absorption and (b) intensity of ma-
jor peaks of Bzim-CP as a function of pH, revealing three ioniza-
tion states. (c) Normalized CD signal (dots) compared to nonpro-
tonated/protonated ratio predicted by the Henderson-Hasselbalch
equation (dotted line) as a function of pH. Inset: corresponding
CD spectrum, suggesting CPN dissociation
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erties affect transport. The CPN in this work complements
the already existing library of hydrophobic CPNs, bringing
the field one step closer to achieving organic nanotubes with
variable and dynamic interiors for better molecular recogni-
tion and transport.
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Acknowledgement
This research was supported through the Center for Gas Sep-
arations Relevant to Clean Energy Technologies, an Energy
Frontier Research Center funded by the US Department of
Energy, Office of Science, Office of Basic Energy Sciences un-
der Award DE-SC0001015. Portions of the work -including
dipeptide 6 synthesis, CP synthesis, and tandem deprotec-
tion and Bzim cyclization- were carried out at the Molecular
Foundry, which is supported by the Office of Science, Office
of Basic Energy Sciences, of the U.S. Department of En-
ergy under Contract No. DE-AC02-05CH11231. We also
acknowledge the support of the Office of Naval Research
(Grant # N00014-13-1-0760) and the National Science Foun-
dation’s Designing Materials to Revolutionize and Engineer
our Future (DMREF) Award CBET-1234305.
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Supporting Information Avail-
able
Experimental procedures and characterization data for all
new compounds.
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