C-9/12 Ribbon-Like Structures in Hybrid Peptides Alternating - and Thiazole-Based -Amino Acids

Abstract

According to their restricted conformational freedom, heterocyclic γ-amino acids are usually considered related to Z-vinylogous γ-amino acids. In such a context, oligomers alternating α- and thiazole-based γ-amino acids, named ATCs were expected to fold into a canonical 12-helical shape as described for α/γ-hybrid peptides composed of cis α/β-unsaturated γ-amino acids. However, we herein demonstrate by combining X-ray crystallography, NMR and FT-IR experiments and DFT calculations that the folding behavior of ATC-containing hybrid peptides is much more complex. While the homochiral α/(S)-ATC sequences were not able to adopt a stable conformation, heterochiral α/(R)-ATC peptides displayed original ribbon structures stabilized by unusual C9, C12-bifurcated hydrogen bonds. These ribbon structures that could be considered as a succession of pre-organized γ/α dipeptides may provide the basis for designing original α-helix mimics.

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A Journal of
Accepted Article
Title: C9/12-ribbon-like structure in hybrid peptides alternating α- and
thiazole-based γ-amino acids
Authors: Clément Bonnel, Baptiste Legrand, Matthieu Simon,
Jean Martinez, Jean-Louis Bantignies, Young Kee Kang,
Emmanuel Wenger, François Hoh, Nicolas Masurier, and
Ludovic Thierry Maillard
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To be cited as: Chem. Eur. J. 10.1002/chem.201704001
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C9/12-ribbon-like structure in hybrid peptides alternating α- and
thiazole-based γ-amino acids
Clément Bonnel,[a]‡ Baptiste Legrand,[a]‡ Matthieu Simon,[a] Jean Martinez,[a] Jean-Louis Bantignies,[b]
Young Kee Kang,[c] Emmanuel Wenger,[d] Francois Hoh,[e] Nicolas Masurier,[a] Ludovic T. Maillard*[a]
Abstract: According to their restricted conformational freedom,
heterocyclic γ-amino acids are usually considered related to Z-
vinylogous γ-amino acids. In such a context, oligomers alternating α-
and thiazole-based γ-amino acids, named ATCs were expected to
fold into a canonical 12-helical shape as described for α/γ-hybrid
peptides composed of cis α/β-unsaturated γ-amino acids. However,
we herein demonstrate by combining X-ray crystallography, NMR
and FT-IR experiments and DFT calculations that the folding
behavior of ATC-containing hybrid peptides is much more complex.
While the homochiral α/(S)-ATC sequences were not able to adopt a
stable conformation, heterochiral α/(R)-ATC peptides displayed
original ribbon structures stabilized by unusual C9, C12-bifurcated
hydrogen bonds. These ribbon structures that could be considered
as a succession of pre-organized γ/α dipeptides may provide the
basis for designing original α-helix mimics.
Introduction
Substantial progress has been made over the last decades
in establishing abiotic architectures, named foldamers,
displaying helices, sheets and ribbon shapes.[1] Initial works
have focused on pseudopeptide oligomers[2] comprising of a
single type of monomer subunits that mainly consist in β-, γ-,
and δ-amino acids (selected examples:[3]) and on backbones
closely related to peptides such as peptoids or oligourea
(selected examples:[4]). In addition to homogeneous oligomers,
hybrid skeletons composed of different types of monomer units,
typically a combination of α, β or γ amino acids permit to explore
unusual folding patterns offering distinct ways to project side
chains in the three dimensional space.[5] Following the
development of α/β-hybrid peptides[2d, 3b, 6] and stimulated by a
systematic conformational analysis,[7] the 12-[8] and the mixed
12/10 helix[9] have been recognized as the most stable
conformations for (α/γ)n peptides.[10] More lately, Gopi et al.
described that α/γ-hybrid peptides composed of Aib and cis α/β-
Scheme 1. Scheme Caption. Chart 1. Nomenclature used for ATCs and
torsion angles description. Dipeptides 1 and 2, and oligomers 3-9.
unsaturated γ-amino acids also accommodate a 12-helical
shape. Surprisingly, the cis double bonds and the carbonyl
groups in the Z-vinylogous residues are not π-conjugated and
largely deviate from the planarity (Table 1).[11]
We have recently described a class of constrained heterocyclic
γ-amino acids named ATCs built around a thiazole ring that were
used to template C9-helical γ-peptide foldamers.[12] Because the
ζ torsion angle is locked around 0°, ATCs are related to Z-
vinylogous γ-amino acids (Chart 1).[13] In line with these studies,
we herein explored the structural feature of sequences
alternating α-amino acids and (S)- or (R)-ATCs using XRD,
NMR and FT-IR spectroscopies, and DFT calculations. Our
results demonstrate that, compared to other γ-amino acids
including constrained vinylogous building-blocks, ATC residues
show unique conformational properties resulting from its
aromatic ring.
Results and discussion
We first explored the intrinsic conformational behavior of the
(γ/α) dipeptide subunit. The two diastereomers Z(2-Br)-(S/R)-
ATC-Phe-NH-iPr 1 and 2 differing by the absolute
stereochemistry of the γ-amino acid (Chart 1) were prepared
NS
R2
O
R1
N
H
O
R1
N
Hα
γβ
φζψθ α
γβ
NS
O
N
H
N
HO
Ph
NS
O
HN H
N
H
N
O
O
O
Br
Ph
n
(S-)Phe-(S-)ATC
3: n = 2
*
NS
O
N
H
N
HO
NS
O
HN H
N
O
n
Ph
*
Ph
O
O
O
(R-)ATC-(S-)Phe
7: n = 1
8: n = 2
9: n = 3
(αγ)n alternating sequences
(S-)Phe-(R-)ATC
4: n = 1
5: n = 2
6: n = 3
(γα)n alternating sequences
N
HO
H
N
N
H
O
NS
O
O
Br
Ph
*
1: (S-)ATC
2: (R-)ATC
ATC building-block
Z-vinylogous
γ-amino acid
[a] Dr. C. Bonnel, Dr. B. Legrand, Dr. M. Simon, Prof. J. Martinez, Prof.
N. Masurier, Dr. L. T. Maillard
Institut des Biomolé cules Max Mousseron, UMR CNRS-UM-ENSCM
5247, UFR des Sciences Pharmaceutiques et Biologiques
15 Avenue Charles Flahault, 34093 Montpellier Cedex 5, France
E-mail: ludovic.maill ard@umontpel lier.fr
[b] Prof. J.L. Bantignies
LC2 - UMR 5221 CNRS-UM, Montpellier, France
[c] Prof. Y. K. Kang
Department of Chemistry, Chungbuk National University, Cheongju,
Chungbuk 28644, Republic of Korea
[d] E. Wenger
Laboratoire de Cristallographie, Résonance Magnétique et
Modélisation, Université de Lorraine, CNRS, UMR 7036, Nancy,
FRANCE
[e] Dr. F. Hoh
Centre de Biochimie Structurale, CNRS UMR 5048-INSERM 1054
University of Montpellier, Montpellier, France
Supportin g information for this article is given via a link at the end of
the document.
10.1002/chem.201704001
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COMMUNICATION
Figure 1. A/ Superimposition of the 15 lowest energy NMR structures of 1 (blue) and 2 (green) in CDCl3. The OBn and NH-iPr moieties were omitted for clarity.
RMSD are 0.448 and 0.208 Å respectively. B/ Crystal structures of 1 (blue) and 2 (green). C/ C9/7-, C9- and C9/12-hydrogen bonds accessible to 1 and 2. D/
Variation of the amide proton NMR resonances of 1 and 2 upon the addition of 40% CD3OH in CDCl3 and E/ FT-IR spectra (Black) and deconvolution (Red) of
oligomers 1 and 2 in the amide I region (3 mM in CHCl3).
according to formerly reported procedure[14]. Their structures
were solved by NMR in CDCl3 and CD3OH (Figures 1A, S14 and
S16) and X-ray crystallography (Figures 1B). 1 and 2 displayed
turn-conformations stabilized by a C9-hydrogen bond between
the urethane C=O and the HN-Phe surrounding the ATC
residues. The γ−residues shared similar torsion angle values at
the solution and solid states, in accordance with those
previously reported for ATC oligomers (Table 1). It is noteworthy
that the ATC ψ dihedral angles significantly differed from those
reported in Z-vinylogous-γ-amino acid-containing hybrid peptides
by Gopi et al.[11] Nevertheless, the C-terminal moieties remained
ambiguous. The sets of NOEs were compatible with the
formation of subsequent C7 or C12 hydrogen bonds associated to
a single rotation of the ϕ torsion angle of the α-residue. At the
solid-state, the α-amino acids exhibited extended conformations
(Figure 1B and Table S42) since the ATC C=O and C-terminus
N-H groups participated in the cohesion of the crystals via strong
intermolecular H-bonds. Thus, such crystal packings could
prevent the establishment of intramolecular C7- and C12-
Hydrogen bonds observed in solution. Consequently, based on
NMR and XRD data, 1 and 2 could adopt three different
conformations, named C9/7-, C9/12- and C9-models depending on
the hydrogen-bonding pattern (Figure 1C).
We compared their relative stabilities by calculating the free
energies using DFT methods at the ωB97X-D/def2-TZVP//SMD
M06-2X/6-31G(d) level of theory in chloroform (Table S47). The
strength of hydrogen bonds in the optimized conformers were
then evaluated in terms of the second perturbation energy (ΔE2)
of the lone pair orbitals of the carbonyl oxygen with the
corresponding N−H antibonding orbital using natural bond orbital
(NBO) analysis[15] at the ωB97X-D/def2-TZVP level of theory
(see Supporting information). We found that the C9/12-conformer
folded around a highly strong C9-hydrogen bond (ΔE2 = 10.70
kcal mol−1) was the most preferred for 1 followed by the C9-
conformer (ΔG = 0.89 kcal mol−1 and ΔE2 = 13.56 kcal mol−1).
The C9/7-folding was much less favored with ΔG = 3.78 kcal
mol−1. Conversely, 2 displayed a different conformational
preference with the most preferred conformers being the C9/12
Table 1. Average
φ
, θ and ψ dihedral angles (°) for the γ-amino acids in ATC-
and Z-vinylogous γ-amino acid-containing sequences.
Cpd
φ
θ
ζ
ψ
(S,S)-1
XRD
-69 ± 3
123 ± 2
10 ± 1
-44 ± 1
NMR (CDCl3)
-85 ± 2
115 ± 7
-8 ± 3
-24 ± 5
NMR (CD3OH)
-103 ± 25
110 ± 25
-6 ± 2
-19 ± 7
(R,S)-2
XRD
83
-115
0
29
NMR (CDCl3)
71 ± 6
-118 ± 2
7 ± 2
24 ± 2
NMR (CD3OH)
64 ± 2
-118 ± 1
11 ± 1
26 ± 1
(R,S)-5
NMR (CDCl3)
76 ± 20
-109 ± 12
4 ± 5
17 ± 9
NMR (CD3OH)
91 ± 39
-112 ± 23
6 ± 6
15 ± 13
poly-(S)-
ATC[12]-
[16]
XRD
-78 ± 3
127 ± 14
0 ± 3
-41 ± 4
NMR (CDCl3)
-76 ± 16
128 ± 12
-6 ±5
-28 ± 6
Gopi's[11]a
XRD
-119 ± 4
100 ± 5
0 ± 3
-78 ± 4
a The oligomers reported by Gopi et al. alternate S-vinylogous γ-amino acids
and Aib.
C9#C9#
(S)-ATC'1"
Phe#2#
(R)-ATC'1"
Phe#2#
C9#
C12'
C7'
Phe#2#
(S)-ATC'1"
C9#
C12'
C7'
(R)-ATC'1"
C/#
A/#
B/#
Compound 1
Δδ#(ppm)#
0'
0.2'
0.4'
0.6'
0.8'
1'
1.2'
1.4'
1.6'
ATC1# F2# iPr# ATC1# F2# iPr#
Free#NH#
C12#
C9#
Compound 2
CD3OH#
D/#
Phe#2#
9
7
N
H
(S)(S)
O
H
N
N
H
O
O
Br
Ph
NS
O
9
N
H
(S)(S)
O
H
N
N
H
O
O
Br
Ph
NS
O
9
N
H
(S)(S)
O
H
N
N
H
O
O
Br
Ph
NS
O
12
10
8
6
4
2
0
x10-3
1800 1700 1600 1500 1400
10
8
6
4
2
0
x10-3
1800 1700 1600 1500 1400
1702#cm-1#
Free#CO#(Phe#2)#
1670#cm-1#
Bound#CO#carbamate#
1641#cm-1#
Free#CO#(ATC#1)#
1706#cm-1#
Free#CO#(Phe#2)#
1673#cm-1#
Bound#CO#carbamate#
1643#cm-1#
Free#CO#(ATC#1)#
Wavenumber#(cm-1)# Wavenumber#(cm-1)#
Absorbance#
#
X#10-3#
#x#10-3#
E/#
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COMMUNICATION
Table 2. Relative conformational free energies (ΔG) and hyperconjugation
energies (ΔE2) of conformers for 1 and 2.a
Cpd
Conf
ΔGb
ΔE2c
C9
C12
C7
1
C9
0.89
13.56
C9/12
0.00
10.70
7.70
C9/7
3.78
3.84
8.95
2
C9/7
0.01
17.73
6.12
C9/12
0.00
18.03
0.28
a All energies are in kcal mol-1. b Gibbs free energies were calculated at the
ωB97X-D/def2-TZVP//SMD M06-2X/6-31G(d) level of theory in chloroform
(see computational details in the Supporting Information). c The
hyperconjugation due to charge transfer for each hydrogen bond was
calculated in terms of the second perturbation energy (ΔE2) of the lone pair
orbitals of the carbonyl oxygen with the corresponding N−H antibonding
orbital[15] at the ωB97X-D/def2-TZVP level of theory.
and C9/7 (ΔG = 0.00 and 0.01 kcal mol−1, respectively) although
the latter had more favorable energy (ΔE = −1.65 kcal mol−1) and
enthalpy (ΔH = −1.46 kcal mol−1) than the former. The C9-
conformer was not a local minimum and converged into the C9/7-
conformer after geometry optimization. Whatever the model
considered, the C9-hydrogen bonds were rather strong (ΔE2 =
17.73 and 18.03 kcal mol-1 respectively) compared to the C7 or
C12 (ΔE2 = 6.12 and 0.28 kcal mol-1 respectively) and remained
the main stabilizing feature of the ATC-based structures.
To gather experimental evidences on the intramolecular
hydrogen bonding of 1 and 2, we performed CDCl3/CD3OH NMR
titration. In contrast to CDCl3, CD3OH can form H-bonds with the
compounds that may compete with intramolecular H-bonds. We
could dissociate two different NH behaviors from 1 (Figure 1D –
Table S34). The NH-Phe exhibited small solvent chemical shifts
dependency along the titration (Δδ = 0.39 ppm), indicating its
involvement in the C9-hydrogen bond. By contrast both HN-ATC
and HN-iPr were accessible to the solvent according to their
significant resonance variation upon CD3OH addition (Δδ = 1.34
and 1.44 ppm, respectively). These data strongly support the C9-
model compared to the C9/7-, C9/12-ones. Conversely, 2 displayed
three different NH behaviors (Figure 1D – Table S35). As in 1,
NH-Phe had a small chemical shift variation (Δδ = 0.21 ppm)
while HN-ATC was highly sensitive to CD3OH addition (Δδ =
1.33 ppm). Interestingly, HN-iPr showed an intermediate
comportment (Δδ = 0.78 ppm) denoting a partial protection from
the solvent in line with the C9/7- or C9/12-bifurcated hydrogen
bond models. To definitively ascertain the H-bonding network of
1 and 2 we achieved FT-IR experiments in CHCl3. The spectra
were almost similar for both compounds. The band at 1706-1702
cm-1 was attributed to the free Phe C=O vibration while the high
frequency amide I bands at 1673-1670 cm-1 were assigned to
the urethane (Figure 1E). We showed in a recent study that the
amide I frequencies provide unambiguous structural markers of
the H-bond network for ATC-containing oligomers.[17] According
to this previous work and based on calculation of the vibrational
frequencies at the SMD M06-2X/6-31G(d) level of theory in
chloroform, free ATC carbonyls were expected to give amide I
absorption at ν(CO)>1640 cm-1 (calculated at 1661 and 1677 cm-
1 for C9- and C9/12-conformers of 1, respectively, and at 1660 cm-
1 for C9/12-conformer of 2) while the bounded ATC C=O should
be highly redshifted around 1626 cm- 1 (calculated at 1624 and
1630 cm-1 for C9/7-conformers of 1 and 2, respectively). Bands
were measured at 1643-1641 cm-1 but no vibration was observed
around 1620-1630 cm-1 for both compounds 1 and 2, excluding
that the ATC carbonyl was engaged into a C7-hydrogen bond
with the NH-iPr. Consequently, taking our results all together, we
could conclude that the homochiral dipeptide 1 may adopt a C9-
fold while the heterochiral analog 2 may prefer the C9/12-
conformation. These data are consistent with our previous report
demonstrating that when incorporated in short peptide
sequences, ATC acts as a strong turn inducer stabilized either
by C9- or C9/12 bidentate hydrogen-bond depending on the γ-
amino acid absolute configuration.[16] Interestingly, such a
hydrogen bonding system has been observed by Grison et al.
for peptides incorporating a Z-vinylogous fragment.[13]
After shedding light on the pre-organization of small dipeptides,
we were interested in the folding capacity of homo- and
heterochiral (α/ATC)n oligomers. Hexapeptides 3 and 5 (Chart 1)
were prepared by alternating (S-)phenylalanine and (R)- or (S)-
ATC respectively (See the Supporting Information). Despite
many efforts, crystallization assays were not successful.
Nevertheless, the NMR signals in CDCl3 were well dispersed
and nearly all 1H, 13C and 15N resonances could be assigned for
both compounds, combining homonuclear COSY, TOCSY,
ROESY experiments and heteronuclear 15N-HSQC, 13C-HSQC
at 15N and 13C natural abundance (Tables S6 and S10). Any
chemical shifts variation was observed from 1 to 10 mM
suggesting that no peptide self-association occurred under
analysis conditions. The amide proton signals following the γ-
amino acids were strongly downfield, i.e. from 9.02 to 9.53 ppm
for 3 and from 9.10 to 9.75 ppm for 5. Such a strong NH
deshielding (> 9 ppm) was formerly related to the formation of
the typical C9-hydrogen bonds surrounding the ATC residues.[17]
Also, we detected strong ATC-δCH(i)/PheNH(i+1) and weak
ATC- γCH(i)/PheNH(i+1), ATC-γCH(i)/Phe-αCH(i+1) and ATC-
γCH(i)/Phe-βCH(i+1) correlations which were characteristics of
the C9-turn (Figure 2A).[16-17] In addition, long range
Phe(i)/ATC(i+3) NOEs were observed along the backbone of 3
and 5 (Figure 2B). These data were strong evidences of well-
organized systems in CDCl3, nevertheless the observed strong
ATC-δCH(i)/PheNH(i+1) correlations were not compatible with
the α/γ 12-helix proposed by Gopi et al.[11] In CD3OH, we
detected a similar set of i/i+1 and i/i+3 correlations for the
heterochiral sequence 5, supporting the hypothesis that the
structure remained in methanol. Inversely for the homochiral
hexamer 3, these characteristic long range Phe(i)/ATC(i+3)
crosspeaks disappeared. NOE correlations (Tables S21 and
S24) were then used as distance restraints for NMR structure
calculations using a typical simulated annealing protocol with
AMBER 11.[18] Peptide 3 displayed a non-canonical helical
shape in CDCl3 while calculations did not converged in CD3OH
demonstrating that the homochiral (α/ATC)n did not provide
stable platforms (see Figures S11 and S18). In contrast, the
solution structures of the heterochiral sequence 5 converged into
a well-defined ribbon shape in both CDCl3 (Figure 2D) and
CD3OH (Figure S15). The fold was stabilized by a regular C9/12-
10.1002/chem.201704001
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COMMUNICATION
Figure 2. A/ Typical short range NOE correlations consistent with the formation of a C9-hydrogen bond and characteristic i/i+1 and Phe(i)/ATC(i+3) NOEs
observed along the backbone of 4-6. B/ Hydrogen-bond patterns for heterochiral (α/ATC)n oligomers C/ FT-IR spectra of 4, 5 and 6 in the amide A and amide I
regions (3 mM in CHCl3). D/ Superimposition of the 15 lowest energy NMR structures of oligomers 3-6 in CDCl3 (lateral chains are omitted for clarity). E/
Superimposition of the lowest energy NMR structure (green) and of the DFT-optimized geometries (purple) of oligomer 5 (lateral chains were omitted for clarity).
H-bonding pattern involving the C=O of the α residue (i) and both
the amide protons of the ATC (i+1) and the α amino acid (i+2).
We then optimized the lowest-energy NMR structures of 3 and 5
by DFT calculations at the M06-2X/6-31G(d) level theory and
calculating the solvation free energies at the SMD M06-2X/6-
31G(d) level of theory in chloroform (Figure 2E). RMSD of the
backbone heavy atoms between NMR and DFT structures were
1.00 and 1.06 Å. According to DFT calculations, the heterochiral
hexamer 5 was 4.80 kcal mol−1 more stable in Gibbs free energy
than the homochiral hexamer 3 in chloroform. Conversely, 3 had
a favorable entropic contribution (−TΔS) of −1.57 kcal mol−1 than
5. This indicates that 5 is more rigid than 3. The stabilities of the
C9- and C12-hydrogen bonds were investigated by calculating the
second perturbation energies (ΔE2) of the lone pair orbitals of
the carbonyl oxygen with the corresponding N−H antibonding
orbital at the ωB97X-D/def2-TZVP level of theory (Table S48).
The sum of ΔE2 values of two C9/12-bifurcated and one C9-
hydrogen bonds for 5 was 14.68 kcal mol−1 greater than 3, to
which the largest contribution was due to the C9-hydrogen bond
between Phe(3)-CO with HN-Phe(5). Thus, the ribbon structures
could be regarded as a succession of highly pre-organized α/γ
dipeptides comprising strong C9- and C12-hydrogen bonds
(Figure 2D). Similar NMR data sets were obtained for other
heterochiral α/γ (Chart 1, compounds 4-6) and γ/α sequences
(Chart 1, compounds 7-9). Whatever the lengths, they shared
similar C9/12-ribbon structures (Figures 2B-C and S12-13 and
S15-16) with average backbone torsion angle values
comparable to those measured on the C9/12-model of the (R)-γ/α
dipeptide 2 (Table S44). The lateral chains are distributed along
four projection axes over the γ-peptide backbone. The thiazole
rings belonging to the ATCs (i, i+4) project perpendicularly to the
ribbon plane and are spaced by around 9 Å (Figure 3).
Interestingly, as shown in Figure 3, the substituents (in green) at
the γ-position of ATCs (i, i+4) and the lateral chains of the α-
amino acids (i-1, i+3) are almost aligned on the same face. They
are separated by approximately 5.1 Å, which reminds the α-helix
pitch.
The structural behavior of the α/(R)-ATC 4-6 and (R)-ATC/α
oligomers 7-9 peptides was confirmed by circular dichroism. The
CD signatures of oligomers 4-9 in methanol (Figures S20 and
S21) were similar to those of other ATC-containing peptides
which displayed turn conformations.[16] They exhibited two
positive maxima at 203 and 228 nm and a large negative band
centred at 255 nm. The α/γ or γ/α alternations of similar lengths
have closed CD signal intensities indicated that they were
almost stable. When the temperature was increased up to 55 °C,
A/# B/#
NS
O
N
H
N
HO
NS
O
HN
H
N
O
* *
D/#
4#
5#
6#
C9#
C9#
C12#
C12#
C9#
E/#
5#
C#
N#
N#
N#
C/#
4"
5"
6"
40x10-3
30
20
10
0
Absorbance
1800 1700 1600 1500 1400
Wavenumber (cm-1)
1715$cm-1$
1721$cm-1$
1721$cm-1$
1643$cm-1$
1640$cm-1$
1640$cm-1$
Amide$II$
8x10-3
6
4
2
0
Absorbance
3500 3400 3300 3200 3100
Wavenumber (cm-1)
3227$cm-1$
3225$cm-1$
3223$cm-1$
3417$cm-1$
3420$cm-1$
3420$cm-1$
3387$cm-1$
3382$cm-1$
3378$cm-1$
NS
O
N
H
N
HO
*
> 9.0 ppm
NS
R3
O
N
H
R2
N
H
R1
O
NS
R3
O
HN
R2
H
N
O
R1
*
C9
C12
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COMMUNICATION
Figure 3. A/ Side chain projections along the α/(R)-ATC backbone. B/
Superimposition of the α/(R)-ATC backbone and a canonical α-helix (ribbon).
Substituents of residues (i, i+3) of the α-helix are fleshed-colored.
we observed a slight decrease of the molar ellipticity without
variation in the shape of the spectra. A total recovery of the CD
signal was observed when the temperature was returned to
20 °C, suggesting that the limited thermal loss of structure
induced by higher temperatures was fully reversible. Importantly,
the per-residue molar ellipticity values of the extrema did not
vary with the number of α/γ dipeptides, as previously described
for other ribbon structures.[19] Once again, such result supported
the idea that the ribbon structure was governed by each pre-
organized α/(R)-ATC C9/12-turns. The regular C9/12 H-bond
pattern was finally established by CDCl3/CD3OH NMR titration
experiments and FTIR spectroscopy. As observed on dimer 2
upon CDCl3/CD3OH titration experiments, each peptide showed
three different NH behaviors attributed to the free N-terminus
amides (Δδ > 1.1 ppm), Phe-NH (Δδ ≤ 0.40 ppm) and ATC-NH
(0.40 < Δδ < 0.80 ppm) engaged in C9- and C12-hydrogen
bonding patterns respectively (Tables S36-41 and Figure S10).
The three NH populations were also evidenced by FT-IR
analyses (Figure 3C and Table S52) in the ν(NH) region (3600-
3100 cm-1). The band around 3420 cm-1 was assigned to the
free NH while the lower vibration frequency (~3220 cm-1 )
corresponded to the NH-Phe engaged in strong C9-hydrogen
bonds. The intermediate band at about 3380 cm-1 was assigned
to the NH-ATC forming C12 pseudocycles. Analysis of the amide
I region (1800-1600 cm-1) was also consistent with the C9/12-
ribbon structure (Figure 3C). The high frequency band observed
for oligomers 4, 5 and 6 at around 1720 cm-1 was attributed to
the free urethane C=O group (Table S53). In sequences 7, 8
and 9, the frequency shifted below 1700 cm-1 probably at about
1685 cm-1 due to H-bonding of the urethane C=O (Table S53).
Consequently, the unsymmetrical broad band between 1640-
1670 cm-1 was attributed to a combination of two vibrations
corresponding to bound Phe C=O and free ATC C=O.
Importantly, estimations of positions and contributions of
discrete subcomponent absorptions in the amide I region have
ultimately been achieved using curve-fitting approaches with
Gaussian functions. As reported on Tables S54-S59,
quantitative analysis revealed that contributions of each C=O
perfectly settled the proposed structure. For both series, we
observed a concomitant downshift of the ν(NH) and ν(CO) band
position to lower frequencies along with the increase of the
oligomer size suggesting stronger hydrogen bonds. Interestingly,
for oligomers of identical sizes, the γ/α series seemed to exhibit
a higher conformational stability than the α/γ oligomers. Indeed,
the amide proton resonances were less sensitive upon methanol
addition for the γ/α series in the CDCl3/CD3OH NMR titration,
and their bound NH and CO displayed significantly downshifted
ν(NH) and ν(CO) absorption bands compared to the
corresponding bands in the α/γ series (Figure S10). This could
be explained because, in the α/γ sequences, the first α-amino
acids is not implicated in the hydrogen-bonding network of the
ribbon structure, thus some fraying at the N-terminus may
occurred which slightly affect the overall stability of the edifice.
Conclusions
We showed in this study that (S/R)-ATC/α dipeptides
adopt C9 and C9/12-turns, respectively. While the homochiral
α/(S)-ATC oligomers do not adopt a stable structure, we pointed
out the ability of the pre-organized C9/12-turn to propagate along
repetitive α/(R)-ATC sequences forming unusual ribbon
structure stabilized by C9/12-bifurcated hydrogen bonds.
Moreover, the (R)-ATC/α sequences were more stable than the
α/(R)-ATC ones. This identified structure is different from those
recently described by Gopi et al. for α/γ-hybrid peptides
alternating achiral Aib and Z-vinylogous γ-amino acids which
adopt a 12-helix. Nevertheless, instead of the highly helicogenic
disubstituted Aib residue, we used proteogenic α-amino acids in
order to maximize the diversification points. Thus, at this stage,
it is not clear if the conformational preference of such sequences
is mainly driven by the α-moiety or is specific to the ATC building
block since 1,4-O,S interactions may occurred which strongly
reduced its conformational freedom (ψ ~ 20°).[20] Such question
is currently under study.
Experimental Section
Commercially available reagents and solvents were used without any
further purification. Reactions were monitored by Thin-Layer
Chromatography (TLC) and analytical HPLC. Products were purified by
column chromatography on a Merck Kieselgel 60 (230-400 mesh) or by
flash column chromatography of silica gel using a Biotage Isolera One
system. Analytical TLCs were run on Merck Kieselgel 60F254 plates.
Visualization was accomplished by UV light (254 nm) and by heating at
300°C after spraying with a commercial phosphomolybdic acid solution
(20% in EtOH). Analytical HPLC analyses were run on an Alliance HT
Waters 2795 separations module equipped with a Chromolith Speed Rod
RP-C18 185 Pm column (50 x 4.6 mm, 5 µm) with a gradient from 100%
(H2O/TFA 0.1%) to 100% (CH3CN/TFA 0.1%) in 3 min; flow rate 5
mL/min; UV detection was done at 214 and 254 nm with a Waters 996
Photodiode Array Detector. Retention times are reported as follows: Rt =
N
S
O
NH
NH
ON
S
O
H
N
HN
O
NH
O
N
S
ONH
O
NH2
N"
C"
N"
C"
5.3$Å$
4.4$Å$
5.7$Å$
A/$ B/$
90°$
90°$
10.1002/chem.201704001
Accepted Manuscript
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This article is protected by copyright. All rights reserved.

COMMUNICATION
(min). LC/MS analyses were recorded on a Quattro micro™ ESI triple
quadrupole mass spectrometer (Micromass, Manchester, UK) equipped
with a Chromolith Speed Rod RP-C18 185 Pm column (50 x 4.6 mm, 5
µm) and an Alliance HPLC System (Waters, Milford, USA); gradient from
100% (H2O/HCO2H 0,1%) to 100% (CH3CN/HCO2H 0,1%) in 3 min;
flowrate 3 mL/min; UV detection at 214 nm. High-Resolution Mass
Spectrometric analyses were performed with a time-of-flight (TOF) mass
spectrometer fitted with an Electrospray Ionisation source (ESI) in
positive ion mode. 1H NMR and 13C NMR spectra were recorded at room
temperature (r.t.) on a Bruker 400 spectrometer at 400.13 MHz and
100.62 MHz respectively; chemical shifts (δ) are reported in parts per
million (ppm) relative to the solvent [1H: δ (CDCl3) = 7.26 ppm; 13C: δ
(CDCl3) = 77.16 ppm; 1H: δ (DMSO-d6) = 2.50 ppm; 13C: δ (DMSO-d6) =
39.52 ppm]. NMR spectra are reported as follows: δ (signal multiplicity,
coupling constant(s), number of protons, numbered protons). 1H NMR
signal multiplicities are designated as broad (br), singlet (s), doublet (d),
doublet of doublet (dd), triplet (t), triplet of doublet (td), quadruplet (q),
quintet (quin), multiplet (m), broad multiplet (brm), sextet (sext), octuplet
(oct), nonet (non).
Synthesis of compounds 1-9: Fmoc-(S)- and (R)-ATC-OH were
prepared according to reported procedures.[14] Syntheses of peptides 1-9
are described in the Supporting Information.
NMR experiments and simulated annealing protocol: The NMR
samples contained 2 mM of (1)-(9) dissolved in CDCl3 and CD3OH.
Spectra were recorded on a Bruker Avance 600 AVANCE III
spectrometer equipped with a 5 mm quadruple-resonance probe (1H, 13C,
15N, 31P). Homonuclear 2D spectra DQF-COSY, TOCSY (DIPSI2) and
ROESY were typically recorded in the phase-sensitive mode using the
States-TPPI method as data matrices of 256-512 real (t1) × 2048 (t2)
complex data points; 8-48 scans per t1 increment with 1.0 s recovery
delay and spectral width of 7210 Hz in both dimensions were used. The
mixing times were 80 ms for TOCSY and 350 ms for the ROESY
experiments. In addition, 2D heteronuclear spectra 13C and 15N-HSQC
were acquired to assign 15N and 13C resonances (32-96 scans, 64-256
real (t1) × 2048 (t2) complex data points). Spectra were processed with
Topspin (Bruker Biospin) and visualized with Topspin or NMRView on a
Linux station. The matrices were zero-filled to 1024 (t1) x 2048 (t2) points
after apodization by shifted sine-square multiplication and linear
prediction in the F1 domain. Chemical shifts were referenced to the
tetramethylsilane (TMS). 1H chemical shifts were assigned according to
classical procedures. NOE cross-peaks were integrated and assigned
within the NMRView software. The volume of a ROE between methylene
pair protons was used as a reference of 1.8 Å. The lower bound for all
restraints was fixed at 1.8 Å and upper bounds at 2.7, 3.3 and 5.0 Å, for
strong, medium and weak correlations, respectively. Pseudo-atoms
corrections of the upper bounds were applied for unresolved aromatic,
methylene and methyl protons signals as described previously. Structure
calculations were performed with AMBER 11 in two stages: cooking and
simulated annealing (SA). The cooking stage was performed at 1000 K to
generate 100 initial random structures. SA calculations were carried
during 20 ps (20000 steps, 1 fs long). First, the temperature was risen
quickly and was maintained at 1000 K for the first 5000 steps, then the
system was cooled gradually from 1000 K to 100 K from step 5001 to
18000 and finally the temperature was brought to 0 K during the 2000
remaining steps. For the 3000 first steps, the force constant of the
distance restraints was increased gradually from 2.0 kcal mol-1.Å to 20
kcal.mol-1.Å. For the rest of the simulation (step 3001 to 20000), the force
constant is kept at 20 kcal.mol-1.Å. The 15 lowest energy structures with
no violations > 0.3 Å were considered as representative of the peptide
structure. The representation and quantitative analysis were carried out
using MOLMOL and PyMOL (Delano Scientific). Ptraj were used to
measure the dihedrals angles.
DFT calculations: All DFT calculations have been performed using the
hybrid-meta-GGA M06-2X functional[21] implemented in the Gaussian 09
program.[22] For (1) and (2), the lowest-energy NMR structures with C9/7-
and C9/12-hydrogen bonds and crystal structures with the C9-hydrogen
bond were used as initial structures for optimization. For 2, the gauche+
and gauche- torsions of the Phe2 residue were also considered for the
initial structures to obtain the feasible local minima. In addition, lowest-
energy NMR structures with two C9/12- and one C9-hydrogen bonds of (3)
and (5) were used as initial structures for optimization. All Br atoms of N-
terminal Cbz groups were replaced by H atoms. First, all initial structures
of (1), (2), (3) and (5) were optimized at the M06-2X/6-31G(d) level of
theory. For (1) and (2), further optimizations were performed in
chloroform using the solvation model based on the density (SMD)
method[23] at the M06-2X/6-31G(d) level of theory. The vibrational
frequencies of local minima of (1) and (2) in chloroform were calculated
at the SMD M06-2X/6-31G(d) level of theory at 25 °C and 1 atm.
However, the vibrational frequencies of local minima of (3) and (5) were
calculated at the M06-2X/6-31G(d) level of theory at 25 °C and 1 atm and
single-point energies in chloroform were calculated at the SMD M06-
2X/6-31G(d) level of theory. Each local minimum was confirmed by
verifying the absence of imaginary frequencies after the frequency
calculations. The scale factor used was 0.9323 at the M06-2X/6-31G(d)
level of theory; this value was chosen to reproduce the experimental
frequency at 1653 cm−1 for the amide I band of the free carbonyl group of
the C-terminal end of Ac-(S)-ATC-NHiPr in chloroform.[17] To obtain the
new scale factor, the C9-hydrogen bonded structure of Ac-(S)-ATC-NHiPr
was optimized in chloroform at the SMD M06-2X/6-31G(d) level of theory
and followed by the frequency calculation. In addition, single-point
energies were calculated using the wB97X-D functional[24] with the larger
def2-TZVP basis set[25] to improve the conformational energies. Zero-
point energy and thermal energy corrections were employed to calculate
the Gibbs free energy of each conformation. Here, the ideal gas, rigid
rotor, and harmonic oscillator approximations were used for the
translational, rotational, and vibrational contributions to the Gibbs free
energy, respectively.[26] The strengths of hydrogen bonds in local minima
of (1), (2), (3) and (5) were evaluated in terms of the second perturbation
energy (ΔE2) of the lone pair orbitals of the carbonyl oxygen with the
corresponding N−H antibonding orbital using natural bond orbital (NBO)
analysis[15] at the wB97X-D/def2-TZVP level of theory.
FT-IR experiments: Middle-infrared experiments (400-5000 cm-1) were
recorded in the transmission mode. The measurements were carried out
on a Bruker Tensor 27 spectrometer equipped with a deuterated (L)-
alanine doped triglycene sulphate (DLATGS) pyroelectric detector, a
Globar source, and potassium bromide (KBr) beam splitter. The spectral
resolution was 4 cm-1, and 128 scans were co-added for each spectrum.
The compounds were dissolved at 1 mM or 3 mM concentration in CHCl3
transferred in a liquid cell equipped with CaF2 windows separated by a
teflon spacer (thickness: 50 µM). A spacer thickness of 50 µM provide
exploitable signal in term of signal-to-noise ratio S/N (S/N (Peak to peak
= 4x10-5), S/N (quadratic mean (RMS) = 1x10-5 between 2000 and 2100
cm-1). Bellow this value, significant compensation problems between
solvent spectral bands used as reference and sample spectrum appear.
The FT-IR spectra were not smoothed. Baseline substraction and
deconvolution were performed using IGOR Pro 6.0 software
(WaveMetrics).
Circular dichroism (CD): CD experiments were carried out using a
Jasco J815 spectropolarimeter. The spectra were obtained in MeOH
using a 1 mm path length CD cuvette, at 20°C, over a wavelength range
of 190-300 nm. Continuous scanning mode was used, with a response of
1.0 s with 0.2 nm steps and a bandwidth of 2 nm. The signal to noise
ratio was improved by acquiring each spectrum over an average of two
scans. Baseline was corrected by subtracting the background from the
sample spectrum. The samples were dissolved in aspectrophotometric
grade MeOH at 100-200 µM.
10.1002/chem.201704001
Accepted Manuscript
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COMMUNICATION
Acknowledgements
Thanks to funding provided by the ANR (French National
Research Agency) – CatFOLD Project. The authors also thanks
the Pôle Chimie Balard and the labex CheMISyst which financed
collaborative exchanges between Montpellier University
(France) and Chungbuk National University (Republic of Korea).
Keywords: keyword 1 • keyword 2 • keyword 3 • keyword 4 •
keyword 5
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10.1002/chem.201704001
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This article is protected by copyright. All rights reserved.

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Entry for the Table of Contents (Please choose one layout)
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A ribbon structure in hybrid peptides
alternating α- and thiazole-based γ-
amino acids
Author(s), Corresponding Author(s)*
Clément Bonnel, Baptiste Legrand,
Matthieu Simon, Jean Martinez, Jean-
Louis Bantignies, Young Kee Kang,
Emmanuel Wenger, Francois Hoh,
Nicolas Masurier, Ludovic T. Maillard*
Page No. – Page No.
C9/12-ribbon-like structure in hybrid
peptides alternating α- and thiazole-
based γ-amino acids
N
S
O
NH
NH
ON
S
O
H
N
HN
O
NH
O
N
S
ONH
O
NH2
N"
C"
N"
C"
90°$
90°$
10.1002/chem.201704001
Accepted Manuscript
Chemistry - A European Journal
This article is protected by copyright. All rights reserved.