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AngewandteInternational Edition
A Journal of the Gesellschaft Deutscher Chemiker
www.angewandte.orgChemie
Accepted Article
Title: Self-assembled Oligopeptide as a Versatile NMR AlignmentMedium for the Measurements of Residual Dipolar Couplings inMethanol
Authors: Xinxiang Lei, Feng Qiu, Han Sun, Liwen Bai, Wen-XuanWang, Wensheng Xiang, and Hongping Xiao
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201705123Angew. Chem. 10.1002/ange.201705123
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Self-assembled Oligopeptide as a Versatile NMR Alignment
Medium for the Measurements of Residual Dipolar Couplings in
Methanol
Xinxiang Lei*, Feng Qiu, Han Sun, Liwen Bai, Wen-Xuan Wang, Wensheng Xiang and Hongping Xiao
Residual dipolar coupling (RDC) constitutes a powerful structural
parameter for the determination of constitution, conformation and
configuration of organic molecules. Here, we report the first liquid
crystalline based orientating medium that is compatible with MeOH,
thus enabling RDC acquisitions of a wide range of intermediate to
polar organic molecules. The liquid crystals were produced by the
self-assembled oligopeptide nanotubes (AAKLVFF), which are
stable at very low concentration. The presented alignment medium
is highly homogeneous and the size of RDCs can be scaled with the
concentration of the peptide. To assess the accuracy of the RDC
measurement by employing this newly introduced medium, seven
bioactive natural products from different classes were chosen and
analyzed. The straightforward preparation of the anisotropic
alignment sample will offer a versatile and robust protocol for the
routine RDC measurement of natural products.
Residual dipolar coupling (RDC) is a highly valuable structural
parameter for biomacromolecules[1] as well as small organic
molecules[2] with respect to constitution, conformation,
configuration and structural dynamics. The application of RDC
for organic compounds has been significantly accelerated owing
to the recent progresses on the development of new pulse
sequences, alignment media and analysis methods.[3]
A prerequisite for RDC measurement is the availability of
suitable alignment media for introducing the necessary
anisotropy to the analytes. Two main classes of alignment media
have been introduced to organic molecules, which are stretched
polymer gels and lyotropic liquid crystalline (LLC) phases.[3e-h]
Polymer gels have been widely applied for acquiring anisotropic
NMR data, as various polymer based media have been
developed for different organic solvents.[4] Notably, Luy et.al
proposed a robust cross-linked poly(ethylene oxide) (PEO) gel,
which is until now the only orienting medium that covers a wide
range of solvent compatibility.[5] LLCs are another good option to
align small molecules because of their excellent NMR
spectroscopic properties and their ability to simultaneously align
organic molecules. However, most of the LC phases e.g.
PBLG,[2c] polyguanidines,[6] polyisocyanates,[7] polyacetylenes,[8]
polyisocyanopeptides[9] are only compatible with aploar solvents
such as chloroform or a mixture of CDCl3 with polar solvents[10],
while a few phases such as ACHC-rich β-peptides[11] and
disodium cromoglycate[12] are compatible with water. In our
previous work, we proposed a series of graphene oxide based
LLCs as orienting media for polar solvents such as
dimethylsulfoxide (DMSO)[13]. Nevertheless, to best of our
knowledge, until now there is still no LC phase that is compatible
with methanol (MeOH), which is a very frequently used solvent
in natural product chemistry, as it is compatible with a wide
range of molecule classes including alcohol, carboxylic acid,
amine and ester. Our aim was therefore to develop a new
methanol compatible LLC phase, which is stable at sufficiently
low critical concentrations and simultaneously can be produced
easily in large scale.
Recently, self-assembled oligopeptides have attracted
immense attention due to their potential applications in
biomedicine, biomimetic materials and nanotechnology.[14]
Various hierarchical architectures including nanofibrils,
nanotubes, nanowires using peptide building blocks have been
developed in the last few years.[14] Inspired by filamentous Pf1
bacteriophage[15] and DNA-nanotube[16] as excellent orientational
ordering media in aqueous solution, we started our
investigations on self-assembled peptides that are soluble in
organic solvents. In fact, several oligopeptide based anticancer
drugs such as nafarelin, detirelix, and leuprolide, have been
shown to form lyotropic liquid crystalline phases with β-sheet
rod-like architecture.[17] More interestingly, Hamley and co-
workers developed a peptide nanotube, which can form a
nematic phase at 1 wt % concentration in methanol.[18] This self-
assembled oligopeptide has the sequence of AAKLVFF, which
was derived from a fragment of the amyloid β-peptide Aβ-(16-
20), KLVFF, whose structure and properties have been
systematically investigated. Furthermore, the self-assembly
mechanism and the formation of nematic phase in methanol of
AAKLVFF has been comprehensively studied. Last but not least,
synthesis of this natural amino acids derived short peptide is
straightforward and the peptide can be produced in large scale.
All of these aspects indicate that AAKLVFF peptide could be an
ideal alignment medium for MeOH solvent.
We observed a birefringent texture of 40 mg/mL AAKLVFF
peptide in methanol using polarized optical microscopy (Figure
S1), which is in accordance with previous studies revealing the
formation of a nematic phase of the peptide at sufficient high
concentration [19]. To further monitor the completeness of the
phase transition and evaluate the anisotropic properties of
AAKLVFF peptide as an alignment medium, 2H NMR spectra of
the medium with different peptide concentration were recorded.
The quadrupole splitting of deuterated MeOH signals
augmented while the concentration of the peptide was
increased, indicating that the strength of the alignment can be
tuned through adjustment of the medium concentration (Fig. S2).
At a concentration of 40 mg/mL, quadrupolar couplings of 18.3
Hz and 2.8 Hz were observed for OD and CD3, respectively. The
doublet 2H NMR signals are sharp and highly symmetric, with a
[∗ ] Prof. Dr. X. Lei, F. Qiu, L. Bai, W.X. Wang
School of Pharmaceutical Sciences, South Central University for
Nationalities, Wuhan, 430074, P. R. China
E-mail: [email protected]
Dr. H.Sun,
Leibniz-Institut fur Molekulare Pharmakologie (FMP), Robert-
Roessle-Strasse 10, 13125 Berlin, Germany
Prof.W. Xiang
School of Life Science, Northeast Agricultural University, Harbin,
Heilongjiang Province 150030, China
Prof.H.Xiao
College of Chemistry & Materials Engineering, Wenzhou University,
Wenzhou 325035, P. R. China
Supporting information for this article is given via a link at the end of
the document.
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line width of 4.1 Hz for OD and 1.2 Hz for CD3 signals,
respectively (Fig S3). This result suggested that the alignment
media prepared with AAKLVFF nanotubes are highly
homogenous with low viscosity, which allows us to shim the
NMR samples as easy as with isotropic solution.
Scheme 1. Molecular structures of the peptide AAKLVFF and a series of
analytes for NMR measurement.
Figure 1. (a) A photograph of AAKLVFF powder in a NMR tube and a solution
of it with MeOH. (b) 2H NMR spectrum (92.1 MHz) of the anisotropic sample
(40 mg/mL peptide LC phase in MeOH), a 2H quadrupolar splitting of 18.30 Hz
of OD was observed.
To show the compatibility and applicability of the AAKLVFF
nanotube as an applicable alignment medium for the acquisition
of high quality RDC data, we selected a series of natural
products with different polarities, functionalities, and structural
complexities. The structural formula of the test compounds 1-7
are shown in Scheme 1. Artemether 1 is a drug used for the
treatment of malaria diseases and it is a derivative of
artemisinin, the discovery of which was awarded for Nobel prize
in 2015. Dihydroartemisinin has been employed as a test
compound for the RDC measurements and analysis in our
previous study.[13b] Gibberellin 2 is a diterpenoid acid and serve
as a hormone that regulates growth and influences various
developmental processes in plants. Ingenol 3 is a natural
product that belongs to the class of diterpene. Its derivative
ingenol mebutate is an approved drug for the tropical treatment
of actinic keratosis. Ginkgolide B 4 is a biologically active
terpenic lactone with six fused five-membered rings.
Actinomycin D 5 is a polypeptide antibiotic that currently used in
the chemotherapy medication for a number of types of cancers.
Furthermore, we selected two small aromatic compounds, which
are indole-3-acetic acid 6 and aristolochic acid A 7 for testing the
compatibility of AAKLVFF peptide with aromatic compounds.
To align the test compounds we used a concentration of 6-
40.0 mg/mL AAKLVFF nanotube, leading to aquadrupolar
coupling of 2.8-21.5 Hz for OD signal. One-bonded proton
carbon couplings of all test compounds were acquired with F2 1H-coupled CLIP-HSQC experiment.[20] RDC values were
directly extracted from the difference between the couplings
measured in isotropic and aligned samples. A portion of the
overlaid CLIP-HSQC spectra of artemether 1 in both conditions
is depicted in Figure S5, showing the well resolved signals under
the aligned condition. It should be noted that the background
signals of AAKLVFF could be observed (Figure S25-26),
although after self-assembling the signal of the monomer was
reduced by 80%. Nevertheless, we did not notice significant
disturbances of them to the solute signals as they are well
separated in the two-dimensional NMR spectra and have sharp
lines. Once the oligopeptide is self-assembled (about 3 days),
the intensity of the background signal does not increase over
time. To further investigate the influence of the background
signals on the signals of analytes, we aligned 5 mg of
polypeptide based natural product actinomycin D (molecular
weight: 1255 gmol-1) in 10 mg/mL AAKLVFF LLC with a
quadrupolar deuterium splitting of 5.7 Hz for OD signal.
Altogether we could measure 26 sets of 1DCH in a range of -17.8
to 9.8 Hz without any overlap between the signals of
actinomycin D and the self-assembled peptide (Fig. 2).
Figure 2. A section of the 600 MHz 1H,13C-CLIP-HSQC spectra of 8 mmol/L
actinomycin D in the isotropic phase (blue contours) and in 10 mg/mL peptide
LCs (anisotropic, red contours).
Taking into account that non-covalent interactions such as
hydrogen bonding, π-π and van-der-Waals interactions are the
driving forces for self-assembly of the peptides, we chose IAA as
a sample compound to investigate its compatibility with the
AAKLVFF nanotube, as IAA contains simultaneously an
aromatic ring, a hydrogen bonding acceptor and donor. We
added 16 mg/mL of the IAA sample into 40 mg/mL of AAKLVFF
nanotube medium. No precipitations or aggregates were
observed. Furthermore, a series of CLIP-HSQC spectra of IAA
were recorded at different concentrations of AAKLVFF (Fig. 3),
revealing that the alignment strength is scaled with the
concentration of the media. Notably, IAA could be aligned at a
LLC concentration of as low as 6 mg/mL, which allows us to
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extract a series of RDCs ranging from -1.8 to 13.9 Hz.
Compared to other established LLC phases, AAKLVFF LLC has
a remarkably low critical concentration. The high scalability of
the AAKLVFF phase makes it a versatile and tunable alignment
medium with broad applicability for small organic molecules.
Figure 3. CLIP-HSQC spectra of IAA at various concentrations of peptides
anisotropic phases.
In addition, our newly introduced alignment medium is stable
at a wide range of temperatures (273-333K) with increasing
alignment strength with decreasing temperature (Figure S22).
Furthermore, we noted that the alignment medium shows an
optimal homogeneity close or below pH 7. Above pH 8, although
the birefringent texture ofthe medium could still be observed, the
viscosity of the medium was increased significantly (Figure S1
and S24).
We further investigate the compatibility of AAKLVFF nanotube
with solvent mixtures such as MeOH/acetone and MeOH/DMSO.
The LLC phase of AAKLVFF nanotube was stable at a maximum
concentration ratio of 40% for acetone and 30% for DMSO,
respectively (Figure S13 and S15). Above the maximum
concentration, self-assembled oligopeptide will be partially
dissolved in the solvent. The RDC measurements of gingkgolide
B and aristolochic acid A were conducted in MeOH/acetone and
MeOH/DMSO solvent mixtures, respectively. Notably, only 1 mg
of the aristolochic acid A sample was used for the RDC
measurement. Furthermore, the analytes can be easily separated
from the AAKLVFF LLC phase by routine column
chromatography, which is a highly important feature for the RDC
measurements of novel natural products with limited availability.
To demonstrate the applicability of AAKLVFF LLC in the RDC-
enhanced structural elucidation of organic molecules, we
validated the structure of five natural products 1-5. IAA 6 and
aristolochic acid 7 are two compounds with planar structure, for
which the alignment tensor cannot be easily determined using the
algorithms implemented in the conventional software packages.
For the RDC fitting, we employed the DFT optimized structures at
B3PW91-D3/pcSeg-1level using X-ray structures of 1,2and 4 as
references[21]. As no X-ray structure was available for ingenol 3,
we modified the X-ray structure of 20-deoxyingenol[22]and further
optimized it with DFT. For actinomycin D 4, a bound conformation
of it with deoxyguanosine was employed in the RDC analysis[23].
We calculated the alignment tensor of each structure using the
singular value decomposition method (SVD)[24] as implemented in
the program package MSpin (http://www.mestrelabs.com)[25].
Theoretically predicted RDCs were determined from the
computed alignment tensor and further compared with the
experimentally calculated ones. The quality factors (Q factors)
between experimental and predicted RDCs for all test compounds
1-5 are close or below 0.2. Artemether, gibberelin and ginkgolide
B are highly rigid molecules with multiple fused rings. All
molecules show excellent fitting between experimental and back-
calculated RDCs with Q factors lower than 0.1 (Table 1). Ingenol
contains partial flexibility in the ring systems, whereas
actinomycin D 4 is potentially flexible with several rotatable
bonds. Considerably low Q factors for both molecules (Q=0.18 for
ingenol and Q=0.20 for actinomycin D) suggested that the X-ray
structure of ingenol and bound conformation of actinomycin D are
the major conformations in solution.
Table 1. A summary of molecule classes, number of experimental RDCs and Q
factor for each test compound.
Compound Numbers
of RDCs
Q factor Condition
number of
SVD
Artemether 11 0.06 16.0
Gibberelin 13 0.04 3.2
Ingenol 12 0.18 4.0
Gingkgolide B 8 0.08 7.2
actinomycin D 26 0.20 5.5
In summary, we presented a liquid crystal forming AAKLVFF
peptide as a versatile alignment medium in organic solvents. This
work is the first example of a MeOH based lyotropic liquid
crystalline as an aligning medium at low critical concentration.
The medium shows high scalability for the precise and accurate
acquisition of RDCs. Seven natural products containing very
different functional groups were measured to demonstrate the
wide compatibility and applicability for the RDC analysis of natural
products. Moreover, the LC phase is highly stable at a wide range
of concentration and temperature, which allow us to precisely
measure molecules with different sizes by varying the degree of
alignment. Furthermore, the synthesis is easy and the medium
can be produced in large scale. We believe the introduced
medium will complement the existing media and enable the RDC
measurements of organic molecules as a routine tool.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (21572164); Key Projects of Technological
Innovation of Hubei Province (No. 2016ACA138). HS and XXL
thank the Sino-German Center for Research Promotion
(GZ1289). The authors thank the Analytical & Measuring Center,
School of Pharmaceutical Sciences, SCUN for their help with
NMR measurements.
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Keywords: residual dipolar coupling•alignment medium •liquid
crystals•self-assembled peptide•NMR spectroscopy
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Layout 1:
COMMUNICATION Alignment medium: A novel, robust, versatile anisotropic medium from self-assembled peptide for the measurement of residual dipolar coupling in MeOH, which are stable at very low concentration. The presented alignment medium is highly homogeneous and the size of RDCs can be scaled with the concentration of the peptide.
Xinxiang Lei*, FengQiu, Han Sun, Liwen
Bai, Wen-Xuan Wang, Wensheng Xiang
and Hongping Xiao
Page No. – Page No.
Self-assembled Oligopeptide as a
Versatile NMR Alignment Medium for
the Measurements of Residual
Dipolar Couplings in Methanol
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