Folding of a linear array of α-amino acids within a helical aromatic oligoamide frame

Article abstract of DOI:10.1021/ja404656z

Control of the spatial organization of proteinogenic side chains is critical for the development of protein mimics with selective recognition properties toward target protein surfaces. We present a novel methodology for producing a linear array of protein

Full text of DOI:10.1021/ja404656z

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Communication
Folding of a Linear Array of #-Amino Acids
within a Helical Aromatic Oligoamide Frame
Mayumi Kudo, Victor Maurizot, Brice Kauffmann, Aya Tanatani, and Ivan Huc
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja404656z • Publication Date (Web): 13 Jun 2013
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Folding of a Linear Array of α-Amino Acids within a Helical
Aromatic Oligoamide Frame
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§,†,¶
†,¶
‡,#,

,§
,†,¶
Mayumi Kudo,
Victor Maurizot, Brice Kauffmann,
Aya Tanatani* and Ivan Huc*
§
Department of Chemistry, Faculty of Science, Ochanomizu University, 2-1-1 Otsuka, Bunkyo-ku, Tokyo 112-8610,
Japan
†
Univ. Bordeaux, CBMN (UMR 5248), Institut Européen de Chimie Biologie, 2 rue Escarpit 33600 Pessac, France
¶
CNRS, CBMN (UMR 5248), France.
‡
Univ. Bordeaux, Institut Européen de Chimie Biologie (UMS 3033/US 001), 2 rue Escarpit, 33600 Pessac, France
#
CNRS, Institut Européen de Chimie Biologie (UMS 3033), France


INSERM, Institut Européen de Chimie Biologie (US 001), France
KEYWORDS Foldamer, Peptide, Structural Investigation, racemic X-ray Crystallography, NMR
Supporting Information Placeholder
appendage of proteinogenic side chains to rigid scaffolds
ABSTRACT: Controlling the spatial organization of protei-
such as linear aryl oligomers (for example terphenyl groups
nogenic side chains is critical to develop protein mimics with
selective recognition properties toward target protein sur-
faces. We present a novel methodology to produce a linear
array of proteinogenic residues based on the incorporation of
α-amino acids into sequences of rigid, helically folded, oli-
goamides of 8-amino-2-quinolinecarboxylic acid (Q). When
5
6
and linear aryl oligoamides) or macrocycles in order to
mimic protein epitopes has also been thoroughly investigat-
ed. In particular, strong emphasis was given in recent years
to linear arrays of side chains at defined intervals that can
mimic the projection of i, i+4 and i+7 residues from one face
7
of an α-helix. Here, we present a novel approach towards
L
-leucine (L) was alternated with dimer Q , the resulting
2
linear arrays of side chains via the incorporation of α-amino
acids into rigid helical aromatic oligoamide frames. The new
folded motifs we have discovered possess a facial polarity and
provide a valuable alternative to currently known examples
of peptide/protein mimics for protein surface recognition or
as amphipathic structures to interact with bilayer mem-
branes.
sequence adopted a right-handed helical conformation, as
deduced in solution from the CD spectra of -(LQ ) (n = 2,
4), and in the solid from X-ray crystallographic analysis of
L
2
n
(
(
±)-(LQ ) . Each LQ segment spanned just one helix turn
2 4 2
pitch of 3.5 Å) and, consequently, the four leucine side
chains of (LQ ) formed a linear array. In solution, NMR
2
4
showed that L-(LQ ) and L-(LQ ) both exist as a mixture of
2 2 2 4
two, slowly equilibrating, folded conformers, the proportion
of which strongly vary with the solvent.
Chart 1. Structures of Q, LQ and (LQ ) oligomers
2
n
Protein tertiary structures and protein-protein recognition
largely rest on intramolecular and intermolecular interac-
tions between α-amino-acid side chains projected at well-
defined positions in space from β-strands, turns and helical
subunits. Controlling the spatial organization of proteino-
genic side chains has thus been a prime objective in peptide
and protein mimetics in order to fine tune their ability to
self-assemble or to interact with protein targets. For exam-
ple, β- and γ-peptides may adopt several types of helical
conformations from which side chains are projected in a
1
variety of arrays distinct from those of α-helical α-peptides.
The possibility to combine α-, β-, and γ-amino acids in the
same helically folded sequences further increases the number
2
of spatial arrays of side chains that can be created. Based on
these helix designs, artificial tertiary or quaternary struc-
Aromatic oligoamide foldamers have emerged as an im-
portant class of folding oligomers characterized by a high
conformational stability and a high predictability of their
3
tures and important steps towards protein surface recogni-
4
tion by non natural sequences have been reported. The
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8
folded conformations. Oligoamides derived from 8-amino-2-
quinolinecarboxylic acid Q (Chart 1) fold into helices having
2.5 units per turn and a pitch of 3.5 Å, as demonstrated both in
showed distinct negative bands at 252.9 nm (ꢀε = –48.3
2 –1 2 –1
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cm mmol ) and 370.0 nm (ꢀε = –19.2 cm mmol ) in CHCl .
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According to previous assignments, the negative band at 370
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15a
the solid state and in solution. These helices are extremely
nm is suggestive of a left-handed helix twist.
L-(LQ ) and
2 2
1
0,9
stable in essentially any solvent. For example, they show
no denaturation at 120°C in DMSO. Their robustness is such
that they can accommodate a number of more flexible ali-
phatic units a priori not prone to folding to which they dic-
tate a folding behavior compatible with the aromatic oli-
L-(LQ ) featured intense CD bands characteristic of a folded
2 4
structure but their signs were reversed from that of
indicating a reversed (right-handed) handedness. The CD
band intensity per LQ repeat units were similar for
L-LQ2
L
-(LQ2)
2
2
and
L-(LQ2)4 which suggests that the extent of folding is
1
1
goamide Qn helix. This contrasts with other examples of
similar for these two species.
hybrid aromatic-aliphatic sequences which often display
novel unexpected folding behaviors.
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α-Amino acids have no apparent feature that would make
them compatible with helically folded Q oligoamides. Nev-
n
ertheless, we were interested in exploring the folding behav-
ior of combinations thereof that would allow to exploit the
robustness of Qn conformations and the wide range of α-
amino acid residues readily available from commercial
sources. Given that a dimer Q spans 0.8 helix turn, we spec-
2
Figure 1. Circular dichroism spectra of 1-4 in CHCl , CH CN
and acetone at 25°C. The horizontal scales have been set to
regions above the absorption range of the solvent.
ulated that an additional α-amino acid, e.g. leucine L, would
3
3
13
allow an LQ segment to span just about one turn, and that
2
repeating this segment in the same sequence would poten-
tially bring the leucine residues in close proximity. In the
following, we report on the synthesis and structural charac-
terization of (LQ2)n oligomers and the discovery that they
adopt helically folded conformations from which the leucine
residues are projected in a linear array from one face of the
helix. The aromatic amide helix provides a rigid frame in
which a certain number of α-amino acids may be inserted
and from which linear arrays of side chains may be projected
for molecular recognition purposes or to build amphipathic
structures.
1
3
The synthesis of (LQ ) oligomers is presented in detail in
2
n
the supporting information. It makes use of optimized mon-
1
4
omer and oligomer synthetic procedures. In short, the main
chain terminal aliphatic amine was protected by a Boc group.
The main chain terminal acid was protected as a 2-
trimethylsilyl-ethyl ester which can be removed in the pres-
ence of fluoride and thus avoid basic conditions that might
racemize leucine α-carbons. The direct coupling of Boc-
leucine to the free amine of a quinoline dimer to give 1
Chart 1) failed in our hands. Even with an acid fluoride acti-
L-
(
vation of leucine, it required long heating times in the pres-
ence of diisopropyl-ethyl-amine that eventually led to race-
mization of the leucine α-carbon (see supporting infor-
mation) On the other hand, the acid fluoride of Boc-L-
leucine could be coupled to an 8-aminoquinoline monomer
to give 4 in 93 % yield without any racemization (Chart 1).
Cleavage of the ester of 4, activation of the resulting acid as
an acid chloride under neutral conditions, and coupling to
another 8-aminoquinoline gave 1. Iterative deprotections of
the N- and C-termini, activation of the terminal acid with
HBTU and coupling to the terminal aliphatic amine then
allowed to prepare 2 and 3 in a convergent fashion. For the
purpose of racemic crystallographic investigations (see be-
Figure 2. Crystal structures of the left handed helix of 1 (a),
and the right-handed helix of 3 (b,c) and molecular model of
an alternate structure of 3 (d,e). Leucine nitrogen atoms and
side chains are shown in blue and gold, respectively. Some
quinoline or carbamate carbonyl oxygen atoms are shown in
red. Some key hydrogen bonds are shown as dashed green
lines. Included solvent molecules, isobutoxy chains, TMSE
groups, tert-butyl groups, and hydrogen atoms have been
omitted for clarity.
low), the synthesis was carried out twice, in the
series.
Preliminary data concerning the conformation behavior of
L and in the
D
these new aliphatic-aromatic hybrids in solution was collect-
ed using circular dichroism (Figure 1). Similar behaviors were
observed in CHCl , acetonitrile and acetone. While
L-LQ (4)
3
showed no CD signal in the 200-400 nm range,
L-LQ (1)
2
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Attempts to grow crystals of 1-3 (single
L-enantiomers)
assigned to two diastereomeric P and M helices, and that
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that would be suitable for x-ray crystallographic analysis all
failed. Our experience with helical aromatic oligomamides is
that racemic or quasi-racemic crystals grow much more
induction of handedness is probably quantitative in the case
of 2 and 3.
1
5
The data above point to the existence of two well defined
non aggregated states having the same handedness. Direct
full NMR assignment and structure elucidation was ham-
pered by broadness and the fact that exchange phenomena
may be difficult to distinguish from NOE correlations. The
sharp spectrum of 2 at 5°C allowed to record COSY spectra
from which the NHs of the central leucine unit were assigned
to two signals at 8.98 and 8.69 ppm for the major and minor
1
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readily, as is the case for other peptides and small pro-
1
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teins. This proved to be valid also in (LQ ) oligomers and
2
n
the structures of rac-LQ and rac-(LQ ) in the solid state
2
2 4
could both be solved in the P-1 centrosymmetrical space
group (Fig. 2). The structure of LQ revealed that the enan-
L
2
tiomer adopts a left-handed helical conformation, consistent
with the sign of the CD band observed in solution (Fig. 1).
The helix is stabilized by a hydrogen bond (d(N-O) = 2.9 Å)
between the N-terminal NH proton and the C-terminal car-
bonyl oxygen atom which are located almost exactly above
each other down the helix axis, confirming the initial as-
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species, respectively. Coupling constants were measured to
3
be J
= 6.9 and 10.5 Hz, for the signals at 8.98 and 8.69
(NH CαH)
ppm, respectively. These values indicate quite different con-
formations of the leucine unit. The large coupling constant
above 10 Hz is the most likely to match with the confor-
sumption that the LQ motif would span one helix turn. This
2
hydrogen bond sets the -leucine φ = –117° and ψ = –5°, re-
L
mation observed in the crystal structure of 3. Indeed the
α
3
sulting in an almost perfect anti conformation of the C H
and NH bonds (179°). The N-terminal carbamate CΟNH
plane is parallel to the helix axis.
Karplus equation applied to J
couplings indicate φ
NH CαH)
(
α
values close to –120° and a C H-NH dihedral angle close to
180° (see supporting information). In contrast, the coupling
In contrast
L
-(LQ ) adopts a right-handed helical confor-
constant at 6.9 Hz may correspond to various φ values near –
160°, –80° or near +60°.
2
4
mation, also in agreement with the sign of its CD band. The
leucine amide NHs (not the carbamate NH) all point toward
the helix axis and hydrogen bond to the endocyclic nitrogen
atom of the neighbor (i–1) quinoline unit. The four LQ seg-
2
ments each account for about one helix turn (pitch of 3.5 Å)
resulting in a linear array of the leucine side chains (see top
view in Fig. 2b) which protrude in an almost perpendicular
α
α
fashion from the helix axis. C –C distances between consec-
utive leucines are 4.8, 4.7 and 4.2 Å starting from the N-
terminus, which is smaller than between i, i+4, and i+7 residues of
α-helices (on average 6.3 Å). Starting from the N terminus, L-
leucines in -(LQ2)4 have φ values of –133, –143, –140 and –155°
L
and ψ values of –5, 26, 40 and 35°, respectively. Such high
negative φ values are common in peptides as they can be found
both in β-sheets and α-helices; the small positive ψ values fall in
an allowed (though not favored) area of the Ramachandran
plot.
NMR studies were carried out to investigate conformations
in solution (Figure 3, see also supporting information). When
1
going from 1 to 3, H NMR spectra show upfield shifts of most
1
Figure 3. Part of the 300 MHz H NMR spectra of 1, and 400
signals, including of terminal groups which indicate increas-
ing and additive effects of ring current effects associated with
π-π stacking. For example, signals of the terminal TMS group
are found at 0.04 , –0.16 and –0.30 ppm for 1, 2 and 3, respec-
1
MHz H NMR spectra of 2 and 3 showing aromatic amide
resonances (10-12 ppm), some aliphatic amide and aromatic
proton resonances (8-9 pmm), and TMS resonances (–0.5-0
ppm). (a) 1 in CDCl at 25°C; (b,c,d) 2 45, 25 and 5°C in
3
tively, in CDCl at 25°C. Such chain-length dependence is
3
CDCl ; (e) 2 at 5° in CD CN; (f) 3 at 25°C in CDCl . The stars
17
3
3
3
typical of folding phenomena. While the spectrum of 1 in
3
indicate two leucine NH protons having very different J
(
NH
CDCl is sharp at 25°C, the spectra of 2 and 3 show some
3
coupling constants.
CαH)
broad signals which sharpen upon heating to 45°C. Upon
cooling, signals of 2 and 3 first broaden further then split into
two sets of sharp signals near 5°C. This behavior indicate the
coexistence of two well-defined species that equilibrate slow-
ly on the NMR time scale. A possible aggregated state was
ruled out as the proportions between these two species do
not depend upon concentration. The proportions, however,
show strong solvent dependence. In the case of 2, propor-
tions of 53:47, 88:12 and 85:15 were measured at 5°C in CDCl3,
CD CN and acetone-d , respectively. Spectra in solvent mix-
The examination of molecular models led to the proposal
of a alternate structure of 3 different from its structure in the
solid state. This model is inspired by the structure of 1 in the
solid state (Figure 2) as it also involves intramolecular hydro-
gen bonds between leucine NH protons of unit i and the
amide carbonyl group of quinoline unit i+2, instead of the
quinoline endocyclic nitrogen atom of unit i–1. When this
pattern is repeated along the four leucines of 3, the corre-
sponding amide functions tilt to planes parallel to the helix
axis and form a linear array of hydrogen bonds reminiscent
of alpha helices. This is accommodated without a change of
the helix pitch (3.5 Å) by a slight increase of the helix diame-
ter and a tilt of the array of leucines with respect to the helix
3
8
tures confirm that the major species is the same in all three
cases. This large variation of proportions contrast with CD
bands which have the same intensity in all three solvents,
indicating that the two species observed by NMR cannot be
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axis. This conformation is very stable in molecular dynamic
simulations (see supporting information) making it a plausi-
ble hypothetical candidate for one of the species observed in
(3) (a) Daniels, D. S.; Petersson, E. J.; Qiu, J. X.; Schepartz, A. J.
Am. Chem. Soc. 2007, 129, 1532. (b) Horne, W. S.; Price, J. L.; Keck, J.
L.; Gellman, S. H. J. Am. Chem. Soc. 2007, 129, 4178.
(4) (a) Michel, J.; Harker, E. A.; Tirado-Rives, J.; Jorgensen, W. L.;
Schepartz, A. J. Am. Chem. Soc. 2009, 131, 6356. (b) Sadowsky, J. D.;
Schmitt, M. A.; Lee, H.-S.; Umezawa, N.; Wang, S.; Tomita Y.;
Gellman, S. H. J. Am. Chem. Soc. 2005, 127, 11966. (c) Boersma, M. D.;
Haase, H. S.; Peterson-Kaufman, K. J. Lee, E. F.; Clarke, O. B.; Col-
man, P. M.; Smith, B. J.; Horne, W. S.; Fairlie, W. D.; Gellman, S. H. J.
Am. Chem. Soc. 2012, 134, 315. (d) Robinson, J. A. ChemBioChem.
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00, 2479. (f) Kritzer, J. A.; Lear, J. A.; Hodsdon, M. E.; Schepartz, A.
J. Am. Chem. Soc. 2004, 126, 9468.
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Hamilton, A. D. J. Am. Chem. Soc. 2002, 124, 11838. (b) Cummings, C.
G.; Hamilton, A. D. Curr. Opin. Chem. Biol. 2010, 14, 341. (c) Plante, J.
P.; Burnley, T.; Malkova, B.; Webb, M. E.; Warriner, S. L.; Edwards,
T. A.; Wilson, A. J. Chem. Commun. 2009, 5091. (d) Yin, H.; Lee, G.–
i.; Sedey, K. A.; Rodriguez, J. M.; Wang, H.–G.; Sebti, S. M.; Hamil-
ton, A. D. J. Am. Chem. Soc. 2005, 127, 5463.
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α
solution. Indeed, in this conformation, leucine C -H and N-H
are eclipsed, leading to φ values of +60°, consistent with the
NMR observations mentioned above.
In summary, sequences combining α-amino acids and
quinoline units Q in the particular (LQQ)n arrangement
gives rise to folded conformation in which linear arrays of
proteinogenic side chains are produced. The next step con-
sist in bringing such sequences into water where aromatic
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oligoamide helical folding is dramatically enhanced
and
where stable patterns might be expected to form. Research in
this direction is in progress and will be reported in due
course.
ASSOCIATED CONTENT
Supporting Information
(6) (a) Park, H. S.; Lin, Q.; Hamilton, A. D. J. Am. Chem. Soc. 1999,
21, 8. (b) Fasan, R.; Dias, R. L. A.; Moehle, K.; Zerbe, O.; Obrecht, D.;
Mittl, P. R. E.; Grütter, M. G.; Robinson, J. A. ChemBioChem 2006, 7,
1
Experimental procedures, full characterization of new com-
pounds, crystallographic data, detailed NMR and CD investi-
gations. “This material is available free of charge via the
Internet at http://pubs.acs.org.”
5
15.
(
7) Wilson, A. J. Chem. Soc. Rev. 2009, 38, 3289
(8) Huc, I. Eur. J. Org. Chem. 2004, 17; Zhang, D.-W.; Zhao, X.;
Hou, J.-L.; Li, Z.-T. Chem. Rev. 2012, 112, 5271.
(9) (a) Jiang, H.; Léger, J.-M.; Huc, I. J. Am. Chem. Soc. 2003, 125,
AUTHOR INFORMATION
3
448. (b) Jiang, H.; Léger, J.-M.; Dolain, C.; Guionneau, P.; Huc, I.
Tetrahedron 2003, 59, 8365. (c) Dolain, C.; Grélard, A.; Laguerre, M.;
Jiang, H.; Maurizot, V.; Huc, I. Chem. Eur. J. 2005, 11, 6135.
Corresponding Author
* E-mail: tanatani.aya@ocha.ac.jp, i.huc@iecb.u-bordeaux.fr
―
(10) (a) Delsuc, N.; Kawanami, T.; Lefeuvre, J.; Shundo, A.; Ihara,
H.; Takafuji, M.; Huc, I. ChemPhysChem 2008, 9, 1882. (b) Qi, T.;
Maurizot, V. Noguchi, H.; Charoenraks, T.; Kauffmann, B.; Takafuji,
M.; Ihara, H.; Huc, I. Chem. Commun. 2012, 48, 6337
Present Addresses
(
Word Style "Section_Content"). †If an author’s address is
different than the one given in the affiliation line, this infor-
mation may be included here.
Notes
(
11) (a) Sánchez-García, D.; Kauffmann, B.; Kawanami, T.; Ihara,
H.; Takafuji, M.; Delville, M.-H.; Huc, I. J. Am. Chem. Soc. 2009, 131,
8642. (b) Baptiste, B.; Douat-Casassus, C.; Laxmi-Reddy, K.; Godde,
F.; Huc, I. J. Org. Chem. 2010, 75, 7175. (c) Delsuc, N.; Poniman, L.;
Léger, J.-M.; Huc, I. Tetrahedron 2012, 68, 4464.
The authors declare no competing financial interest.
ACKNOWLEDGMENT
(
12) (a) Prabhakaran, P.; Kale, S. S.; Puranik, V. G.; Rajamohanan,
This work was supported by the International Training Pro-
gram of JSPS (Predoctoral Fellowship to MK). We thank Dr.
Shigeru Ito for assistance with NMR spectra interpretation.
P. R.; Chetina, O.; Howard, J. A.; Hofmann H. J.; Sanjayan, G. J. J. Am.
Chem. Soc. 2008, 130, 17743. (b) Srinivas, D.; Gonnade, R.; Ravin-
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A.; Prabhakaran, P.; Baruah, P. K.; Sanjayan G. J. Chem. Commun.
2
011, 47, 11593.
(
13) Throughout the manuscript sequences abbreviated (LQ )
2 n
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