Unprecedented torsional preferences in trans-β2,3-amino acid residues and formation of 11-helices in α,β2,3-hybrid peptides

Article abstract of DOI:10.1002/chem.201201415

Anti or gauche? trans-β^2,3-Amino acid residues that are known to promote extended structures in their peptides show specific rotamer preferences in response to an intramolecular hydrogen-bonding possibility, which facilitates the 11-helical structures in their 1:1 α,β-hybrid peptides (see figure). Preferences for the gauche conformation for all internal β residues and anti for the C-terminal residue in these peptides were confirmed by NMR spectroscopic and X-ray diffraction experiments. Copyright

Full text of DOI:10.1002/chem.201201415

COMMUNICATION
DOI: 10.1002/chem.201201415
Unprecedented Torsional Preferences in trans-b2,3-Amino Acid Residues and
Formation of 11-Helices in a,b2,3-Hybrid Peptides
Dhayalan Balamurugan and Kannoth M. Muraleedharan*[a]
Protein folding processes that spontaneously select the
most appropriate combination of backbone torsions to reach
a unique and functionally active three-dimensional structure
continue to puzzle the scientific community. This has in-
spired investigations into the folding preferences of natural
and unnatural oligomers with homogeneous or heterogene-
ous backbones, of which b- and a,b-hybrid peptides remain
the most studied.[1] After early work by Gellman and col-
leagues[2] and Seebach et al.,[3] the field of foldamers[4]—
a term coined by Gellman—has expanded significantly over
the past two decades to hold a central position in chemical
biology, with applications in both medicine and materials
science.[5] Using building blocks such as b2-, b3-, b2,3-, and
ring-constrained amino acids, a variety of secondary struc-
tures such as helices, pleated sheets, and turns have been re-
alized.[1a,6] Inclusion of a-amino acids in the design has re-
sulted in hybrid peptides with ab, abb, and aab residue al-
terations, which have considerably expanded the foldamer
portfolio with a greater range of possible secondary structur-
es.[5c,7] In general, such hybrid systems behave like a-pep-
tides and form i,i+3 hydrogen bonded helices from shorter
oligomers, showing a bias toward i,i+4 hydrogen bonded
helical arrangements on chain elongation.[5a,7e–g] The helix
type depends heavily on the nature and stereochemistry of
substituents at the a- and b-positions, and on oligomer com-
position. The presence of two types of helices along the full
length of the hybrid peptide to give mixed helices, or in sep-
arate but adjacent segments along the backbone to give
hybrid helices, have also been observed which have added
a new dimension to foldamer research.[8]
Figure 1. Representation of a,b2,3-hybrid peptides 1–5 showing the tor-
sional preferences in trans-b2,3-amino acid residues.
gauche conformation in response to the opportunity for in-
tramolecular hydrogen bonding to yield helical structures.
To the best of our knowledge, this represents the first exam-
ple of such a cooperative rotamer preference in trans-b2,3-
amino acid residues to favor a folded secondary structure.
Whilst the conformational profiles of a,b-hybrid peptides in-
volving monosubstituted (b2- or b3-) and cycloalkane-b-
amino acids have been well documented,[1b] hybrids of acy-
clic b2,3-amino acids remain largely unexplored.[7d] Therefore,
the results presented herein, apart from giving access to
a new class of foldamers, bridges the information gap be-
tween these two hybrid peptide classes.
The trans-b2,3-amino acid (b2,3Aa, R,R isomer, Figure 1) in
the orthogonally protected form was accessed through our
previously reported method, which uses an anti-selective
aldol and azide displacement as the key steps.[9] This was
coupled with a-aminoisobutyric acid (Aib) under standard
peptide coupling conditions to prepare hybrids 1 and 2 (Fig-
ure 2a,b). Aib was chosen as the a-amino acid based on its
known propensity to stabilize helical conformations,[1c,10] and
favorable crystallinity/solubility characteristics of the result-
ing peptides.[7e,f,11] The solvent-shielded nature of the inter-
As part of our investigation into the self-organization and
channel-forming ability of laterally amphiphilic molecular
strands based on trans-b2,3-peptides, we synthesized a series
of trans-b2,3-amino acids (b2,3Aa) in acceptable yields and
stereoselectivities.[9] Although such residues are known to
promote an extended conformation in peptides,[6b] the work
presented herein involving hybrid a,b2,3-peptides (Figure 1,
1–5) shows their remarkable ability to shift from anti to the
1
nal NH in tripeptide 1 was evident from H NMR titration
experiments in CDCl3; incremental addition of [D6]DMSO
1
3
(up to 20% v/v) caused significant shifts for NH and NH
2
relative to NH. However, X-ray diffraction analysis of crys-
tals obtained by slow evaporation of the iPrOH solution
showed that an extended conformation is preferred in the
solid state, with an anti-periplanar arrangement of Ca and
[a] D. Balamurugan, Dr. K. M. Muraleedharan
Department of Chemistry
Indian Institute of Technology Madras, Chennai, 600036 (India)
Fax : (+91)44-2257-4202
E-mail: mkm@iitm.ac.in
Cb protons (torsion angle N Cb Ca CO, q=ꢀ1798).[12]
ꢀ
ꢀ ꢀ
1H NMR spectroscopic studies involving compound 2 re-
2
3
4
vealed the solvent-shielded nature of NH, NH, and NH
protons. They respectively appeared at 7.23, 6.87, and
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201201415.
Chem. Eur. J. 2012, 00, 0 – 0
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Figure 2. a–d) Chemical and X-ray crystal structures of peptides 1–4 (side view; stereoview of 4 generated with PyMOL). e) Chemical structure of octa-
ꢀ
peptide 5. Dotted lines in the chemical structures indicate non-sequential NOEs in the ROESY spectra; i,i+3 C=O···H N hydrogen bonds observed in
ꢀ
the crystal structures of 2–4 are shown as solid lines; i,i+3 C=O···H N hydrogen bonds in 5, proposed based on NMR data, are shown as solid lines.
Non-relevant hydrogen atoms and co-crystallized solvent molecules are omitted for clarity. f) Top view of the crystal structures of peptides 1–4. g) Anti
and h) gauche conformations in trans-b2,3-Aa; these conformational states in peptides 1–5 are highlighted respectively in light and dark grey.
7.77 ppm, and solvent titration experiments induced only
or apparent doublet, depending on the relative value of
3JCbHꢀCaH (Figure 2g,h); a larger value favors the former,
and a smaller value the latter. Because an anti-periplanar ar-
very small shifts in these signals (DdNH=0.230–0.237), indi-
1
cating a folded structure. The corresponding value for NH
ꢀ
was higher (DdNH=1.43), indicating its solvent-exposed
nature. The rate of deuterium exchange from a time-de-
pendant NMR experiment in CD3OD was ranked in the
order NH @ NH > NH > NH, confirming that the inter-
nal protons are more solvent-shielded than the terminal pro-
tons. The folding was also evident from the characteristic
splitting patterns of CbH signals in residues 2 and 4. Because
the J value for its coupling with the adjacent amide proton
(3JNHꢀCbH) is relatively large (~10.0 Hz), the expected dd
pattern in these cases can change to either apparent triplet
rangement across the Ca Cb bond facilitates an extended
conformation, the appearance of the CbH signal can be used
to predict the conformational preference. In the case of pep-
tide 2, the signal corresponding to 2CbH appeared as a broad
doublet. Although individual J values could not be deci-
1
4
3
2
3
phered, this suggests a relatively small JCbHꢀCaH value and
a gauche conformational preference. At the same time,
a higher JCbHꢀCaH value was observed for CbH, indicating
an anti-periplanar arrangement of Ca and Cb protons. The
presence of a specific fold in this case became more evident
3
4
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2
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Torsional Preferences in trans-b2,3-Amino Acids
COMMUNICATION
from the long-range NOEs in the ROESY spectrum. The
peptide-coupling protocol. They were characterized through
detailed spectroscopic methods (Supporting Information),
and 1H NMR peaks were unambiguously assigned by 2D
NMR experiments. The deshielded nature of NH signals in
their 1H NMR spectra (d~7.4–8.6 ppm) reveals their in-
volvement in hydrogen bonding. As observed for 2, solvent
titration studies in CDCl3 using [D6]DMSO (up to 30% v/v)
showed that their internal protons are solvent shielded
(DdNH=0.06–0.52; Supporting Information) relative to the
terminal protons (DdNH~1.70).
non-sequential 2CbH! NH and 2CbH! CaH NOEs were
the early signs of the presence of an 11-helical structure.
This was further confirmed when crystals formed from
iPrOH solution were subjected to X-ray diffraction analysis
(Figure 2b).[12] As anticipated based on ROESY results,
peptide 2 exhibited an 11-helical structure through hydrogen
bonding involving Boc-C=O···NH(3) and CO(1)···NH(4)
groups (Boc-C=O···NH(3): H···O=2.09 ꢁ, N···O=2.96 ꢁ,
4
4
ꢀ
]N H···O=1638; CO(1)···NH(4): H···O=2.1 ꢁ, N···O=
ꢀ
2.94 ꢁ, ]N H···O=1578). As anticipated based on the ap-
Hexapeptide 4 exhibited three non-sequential NOEs
4
4
4
6
4
6
pearance of the CbH signal, the C-terminal b residue was
(2CbH! NH, CbH! NH, and CbH! CaH) in its ROESY
spectrum. This, taken in conjunction with the analogous
NOE pattern observed for 2, indicated an 11-helical ar-
rangement. Characteristic splitting patterns of CbH signals
in residues 2, 4, and 6 are also indicative of a specific fold-
ing. In the case of peptide 4, the CbH signals of residues 2
and 4 appeared as apparent doublets at d=5.58 and
5.61 ppm, with respective J values of 10.8 and 10.4 Hz
found in an extended conformation. In comparison with 1,
tetrapeptide 2 possesses just one more b residue at the C ter-
minus. Interestingly, this addition caused the second b unit
to undergo a shift from anti to gauche (q=85.68, Table 1) to
facilitate a more stable helical arrangement.
Table 1. Selected backbone torsion angles of hybrid peptides 1–4.
(3JNHꢀCbH), suggesting
a
gauche conformation (small
3JCbHꢀCaH). The C-terminal b residue, however, appeared as
doublet of doublets with J values of 9.0 and 10.5 Hz, corre-
sponding to a near anti-periplanar arrangement of Ca and
Cb protons. Fortunately, we were successful in crystallizing
peptide 4 by slow evaporation of its CHCl3 solution.[12] Crys-
tallographic analysis confirmed the observations from NMR
studies, and the crystal structure showing the 11-helical ar-
rangement is shown in Figure 2d. Notably, the 2nd and 4th
b residues in 4 prefer the gauche conformation (q=82.7 and
88.58, respectively, Table 1), as opposed to anti, to facilitate
Peptide:
1
2
3
4
Residue:
f
q[a]
2
2
4
2
2
4
6
ꢀ108.4 ꢀ109.3 ꢀ152.3 ꢀ153.1 ꢀ104.3 ꢀ109.4 ꢀ145.1
ꢀ179.0
85.6
ꢀ74.8
ꢀ179.5
84.4
ꢀ73.8
82.7
ꢀ78.6
88.5
ꢀ73.2
ꢀ177.1
y
117.1
126.6
128.6
ꢀ
[a] Values in boldface indicate the gauche conformational preference of
internal b residues.
four intramolecular hydrogen bonds (i,i+3 C=O···H N)
with H···O distances ranging from 2.07 to 2.24 ꢁ; N···O dis-
ꢀ
tances between 2.97 and 3.08 ꢁ, and N H···O angles in the
range of 155–1678, which are in accordance with values re-
ported for other known 11-helical peptides.[7f] The inter-
proton distances from X-ray diffraction data of peptides 2–4
directly correlated with the NOE information from their
ROESY spectra, and are listed in Table 2.
A comparison of the crystal structures of 1 and 2 brought
to light the importance of additional opportunities for intra-
molecular hydrogen bonding in folding. This prompted us to
determine whether the introduction of a C-terminal NH
group, by replacing the benzyl ester with a benzylamide
unit, is capable of inducing folding in tripeptides. To this
end, we made peptide 3 from 1 by debenzylation followed
Table 2. Characteristic NOEs (ROESY) and the interatomic distances
from X-ray diffraction data.
2
by coupling with benzylamine. The CbH signal in this case
Peptide
NOE Type
Distance [ꢁ]
appeared as a broad peak, making it difficult to assess any
torsional preference. Interestingly, this compound showed
4
2
2CbH! NH
2.945
3.651
2.884
3.134
2.751
3.438
4
2CbH! CaH
4
2CbH! NH long-range NOE in its ROESY spectrum. This
4
3
4
2CbH! NH
4
2CbH! NH
compound was later crystallized from a CHCl3/hexane mix-
ture and subjected to X-ray diffraction analysis.[12] As ex-
pected, it was found to adopt an 11-helical structure (Fig-
ure 2c) with the internal b residue in a gauche conformation
(q=84.48, Table 1). The i,i+3 hydrogen bonding distances
and angles are similar to those observed for 2 (Boc-C=
6
4CbH! NH
6
4CbH! CaH
Although our attempts to crystallize octapeptide 5 were
not successful, its NMR profile, which was directly compara-
ble with those of 2 and 4, helped us to unambiguously deter-
ꢀ
O···NH(3): H···O=2.13 ꢁ, N···O=2.96 ꢁ, ]N H···O=1638;
ꢀ
CO(1)···NH(4): H···O=2.0 ꢁ, N···O=2.83 ꢁ, ]N H···O=
1
1588).
mine its secondary structure. H NMR signals were well dis-
To understand the conformational preferences of higher
homologues in this series, peptides with six and eight resi-
dues (4 and 5, respectively) were synthesized by a standard
persed on the d scale, making peak assignments very easy.
As in the case of 2 and 4, the CbH signal from the terminal
residue (8CbH) appeared as a doublet of doublet, with J
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D. Balamurugan and K. M. Muraleedharan
values of 9.5 and 10.4 Hz, indicating an anti-periplanar ar-
rangement of Ca and Cb hydrogen atoms. The signals for
through a gauche-to-anti twist in each of the internal b resi-
dues, such molecules are also useful for studying the folding
and unfolding phenomena in a systematic manner under var-
ious experimental conditions. We previously reported the
solid-state structures of a series of b2,3-amino acid deriva-
tives with some selected hydrogen bond donor–acceptor
moieties at the N and C termini.[15] Whereas that work high-
lighted the cooperative rotamer preferences in the forma-
tion of stable lattice arrangements, the details presented
herein demonstrate how such cooperative effects occur in-
tramolecularly to give stable secondary structures.
2CbH, CbH, and CbH at the same time appeared as appar-
ent doublets at d=5.59, 5.72, and 5.68 ppm, respectively,
showing a preference for the gauche conformation (small
3JCbHꢀCaH). The 11-helical arrangement in 5 was subsequently
confirmed through a ROESY experiment, which clearly
4
6
4
4
showed four distinct long-range NOEs (2CbH! NH, CbH!
6
8
6
8
6NH, CbH! NH, and CbH! CaH): very similar to those
observed for 2 and 4. Inter-proton distances in these cases
were estimated by volume integration of relevant ROESY
cross-peaks.[13] The interatomic distances corresponding to
long-range NOEs turned out to be between 3.2 and 3.6 ꢁ
(Supporting Information), which are in the range expected
for the medium NOEs observed here. The distances estimat-
ed for peptides 2–4 using this method were also in the same
range, further supporting our conformational assignment for
5. The CD spectra of compounds 2, 4, and 5 recorded in
MeOH solution (200 mm) at room temperature had a charac-
teristic two-peak absorption profile with maxima at 198 and
215 nm, as shown in Figure 3. Spectra were normalized for
In summary, we synthesized a series of hybrid peptides
with Aib and trans-b2,3-amino acid (b2,3Aa) at alternate posi-
tions. Detailed NMR and crystallographic analyses involving
ꢀ
peptides 1–5 showed how the Ca Cb torsions in b residues
vary in response to intramolecular hydrogen bonding possi-
bilities and assist in folding. Interestingly, the internal b resi-
dues in peptides 2–5 were found to adopt the gauche confor-
ꢀ
mation to accommodate i,i+3 C=O···H N hydrogen bonds,
which stabilized an 11-helical structure; the C-terminal b re-
sidue in these cases, however, opted for an anti-periplanar
ꢀ
arrangement across the Ca Cb bond. The cooperative rota-
mer preference in response to intramolecular hydrogen
bonding was also evident from the conformational preferen-
ces of peptides 1 and 3. Whilst the benzyl ester 1 adopted
an extended structure in the solid state, introduction of a C-
terminal amide NH group, as in 3, was found to induce a tor-
ꢀ
sional change across the internal Ca Cb and stabilize an 11-
helix. To the best of our knowledge, this is the first demon-
stration of a cooperative rotamer preference from the back-
bone elements of a a,b2,3-hybrid peptide to adopt a specific
11-helical conformation.
Acknowledgements
Financial support of this work by the Department of Science and Tech-
nology (DST), India (Grants SR/S1/OC-13/2007) is gratefully acknowl-
edged. We thank Mr. V. Ramkumar, Department of Chemistry, and Dr.
Babu Vargheese, SAIF (IITM), for X-ray analysis and SAIF (IITM) for
2D NMR data. We thank Dr. N. Jayaraman, Department of Organic
Chemistry IISc Bangalore, and Dr. R. Srinivasan, CLRI Chennai, for CD
data. D.B. thanks the DST and IITM for a research fellowship.
Figure 3. CD spectra of peptides 1–5.
both the number of residues and concentration, and molar
ellipticity [V] is reported in degcm2 dmolꢀ1. Among the tri-
peptide benzyl ester 1 and benzylamide 3, only the former
gave a peak at 198 nm, which is much weaker than that of
peptides 2, 4, and 5. Peptides with phenyl rings are known
to show abnormal CD spectral patterns due to an additional
absorption in the region under study.[14] Thus, the peak at
198 nm, although indicative of a helical structure, is not suf-
ficient for making a quantitative comparison of helicity in
such systems.
Keywords: foldamers
·
helical structures
·
NMR
spectroscopy · a/b-hybrid peptides · b-amino acids
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Torsional Preferences in trans-b2,3-Amino Acids
COMMUNICATION
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[12] Crystal data for 1: C32H45N3O6; Mr =567.71 Da; crystal size 0.25ꢅ
0.22ꢅ0.10 mm; monoclinic; space group P21; a=6.1176(6) ꢁ, b=
26.601(3) ꢁ, c=10.3066(12) ꢁ, a=908, b=97.390(5)8, g=908; V=
1663.3(3) ꢁ3; Z=2; 1calcd =1.134 Mgmꢀ3
;
m=0.078 mmꢀ1
;
l=
0.71073 ꢁ; T=298(2) K; qmax =27.668; reflections collected 7844; in-
dependent reflections 4401 [R(int)=0.0676]; final R indices [I>
AHCTUNGTRENNUNG
2s(I)] R1=0.0668, wR2=0.0868; R indices (all data) R1=0.1564,
wR2=0.1105. Crystal data for 2: C44H62N4O8; Mr =774.98 Da; crys-
tal size 0.30ꢅ0.25ꢅ0.20 mm; orthorhombic; space group P212121; a=
10.5849(5) ꢁ, b=20.2936(13) ꢁ, c=20.4196(14) ꢁ, a=b=g=908;
V=4386.2(5) ꢁ3; Z=4; 1calcd =1.174 Mgmꢀ3
;
m=0.081 mmꢀ1
;
l=
0.71073 ꢁ; T=293(2) K; qmax =21.818; reflections collected 15707;
independent reflections 5227 [R(int)=0.0279]; final R indices [I>
AHCTUNGTRENNUNG
2s(I)] R1=0.0371, wR2=0.0883; R indices (all data) R1=0.0504,
wR2=0.1016. Crystal data for 3: C32H46N4O5; Mr =566.73 Da; crys-
tal size 0.38ꢅ0.32ꢅ0.25 mm; orthorhombic; space group P212121; a=
10.7897(3) ꢁ, b=16.6551(4) ꢁ, c=18.4441(5) ꢁ, a=b=g=908; V=
3314.47(15) ꢁ3; Z=4; 1calcd =1.136 Mgmꢀ3
;
m=0.077 mmꢀ1
;
l=
0.71073 ꢁ; T=298(2) K; qmax =28.388; reflections collected 12994;
independent reflections 6903 [R(int)=0.0181]; final R indices [I>
AHCTUNGTRENNUNG
2s(I)] R1=0.0417, wR2=0.1015; R indices (all data) R1=0.0738,
wR2=0.1173. Crystal data for 4: C63H85N6O9Cl9; Mr =1389.42 Da;
crystal size 0.38ꢅ0.35ꢅ0.15 mm; monoclinic; space group P21; a=
12.0984(6) ꢁ, b=23.9692(12) ꢁ, c=12.9116(14) ꢁ, a=908, b=
104.078, g=908; V=3629.2(3) ꢁ3; Z=2; 1calcd =1.271 Mgmꢀ3; m=
0.402 mmꢀ1
collected 21222; independent reflections 11431 [RAHCTUNGTRENNUNG
;
l=0.71073 ꢁ; T=293(2) K; qmax =25.438; reflections
(int)=0.0251];
final R indices [I>2s(I)] R1=0.0766, wR2=0.2027; R indices (all
data) R1=0.1201, wR2=0.2386. CCDC-819551 (1), CCDC-819552
(2), CCDC-874769 (3), and CCDC-859954 (4) contain the supple-
mentary crystallographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
[13] I. M. Mꢄndity, E. Wꢃber, T. A. Martinek, G. Olajos, G. K. Toth, E.
Vass, F. Fulop, Angew. Chem. 2009, 121, 2205–2209; Angew. Chem.
Int. Ed. 2009, 48, 2171–2175.
[14] S. Brahms, J. Brahms, J. Mol. Biol. 1980, 138, 149–178.
[15] D. Balamurugan, V. Ramkumar, K. M. Muraleedharan, Cryst.
Growth Des. 2010, 10, 2460–2464.
[9] D. Balamurugan, K. M. Muraleedharan, Tetrahedron 2009, 65,
10074–10082.
[10] a) C. Toniolo, E. Benedetti, Macromolecules 1991, 24, 4004–4009;
b) J. Venkatraman, S. C. Shankaramma, P. Balaram, Chem. Rev.
Received: April 25, 2012
Published online: && &&, 2012
Chem. Eur. J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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D. Balamurugan and K. M. Muraleedharan
Hybrid Peptides
D. Balamurugan,
K. M. Muraleedharan* ...... &&&& — &&&&
Unprecedented Torsional Preferences
in trans-b2,3-Amino Acid Residues and
Formation of 11-Helices in a,b2,3-
Hybrid Peptides
Anti or gauche? Trans-b2,3-Amino acid
residues that are known to promote
extended structures in their peptides
show specific rotamer preferences in
response to an intramolecular hydro-
gen-bonding possibility, which facili-
tates the 11-helical structures in their
1:1 a,b-hybrid peptides (see figure).
Preferences for the gauche conforma-
tion for all internal b residues and anti
for the C-terminal residue in these
peptides were confirmed by NMR
spectroscopic and X-ray diffraction
experiments.
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www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!