Induction of unexpected left-handed helicity by an N-terminal L -amino acid in an otherwise achiral peptide chain

Article abstract of DOI:10.1002/anie.201107583

Peptide helices containing L-amino acids are typically right-handed. Exceptions are peptide helices containing the achiral amino acids 2-aminoisobutyric acid and glycine with a single chiral amino acid at the Nterminus. These helices are left-handed when the N-terminal residue is a common tertiary proteinogenic amino acid, such as L-valine (see picture, left), but right-handed when the N-terminal residue is the quaternary amino acid L-α-methylvaline (right). Copyright

Full text of DOI:10.1002/anie.201107583

Angewandte
Chemie
DOI: 10.1002/anie.201107583
Helical Peptides
Induction of Unexpected Left-Handed Helicity by an N-Terminal
l-Amino Acid in an Otherwise Achiral Peptide Chain**
Robert A. Brown, Tommaso Marcelli, Matteo De Poli, Jordi Solꢀ, and Jonathan Clayden*
Helices composed of l-a-amino acids are typically more
stable when they adopt right-handed (rather than left-
handed) helicity, due to steric interactions between the l-
amino acid side chains and the main-chain carbonyl groups.[1]
Left-handed helices are rare motifs in protein structures
(about 0.4% in a nonredundant subset of the Protein Data
Bank), and the vast majority of these helices are short (four
residues at most), stabilized by interhelical hydrogen bonds
and other weak interactions. Many left-handed helices are
important for the stability of the protein, for ligand binding,
or as part of the active site.[2] Collagen is an exception: its
quaternary structure adopts right-handed helicity, but its
individual peptide chains are long single-stranded left-handed
helices, stabilized through intermolecular hydrogen bonds.[3]
Necessarily, all-d proteins,[4] or those synthesized as race-
mates,[5] contain left-handed helical domains.[6]
Peptides made entirely of achiral amino acids, even
though they may form helical structures, can have no
preference for left- or for right-handed helicity. For example,
octamers of the achiral quaternary amino acid Aib (2-
aminoisobutyric acid) form 310 helices that interconvert
rapidly in solution between the left- and right-handed helical
conformations.[7] A single N-terminal l-amino acid is none-
theless sufficient to perturb measurably[8] the conformational
ratio and can induce an absolute helical preference[9] in an
entire chain of up to 20 achiral amino acids.[10] Induction of
helical preference[11] from the terminus of an otherwise
achiral chain, mediated by stabilization of one of the two
helical conformations, has been reported in several other
classes of synthetic foldamers,[12] including dehydropep-
tides,[13] polyisocyanates,[14] polyureas,[15] and aromatic oligo-
amides.[16] Switching the configuration of the chiral terminal
residue switches the helical preference of the entire oligo-
mer,[17] and the literature suggests[9] that in solution an l-
amino acid induces right-handed helicity in an achiral Aibn
peptide chain.[18]
Herein we report a combined NMR spectroscopy, circular
dichroism (CD) spectroscopy, and computational study that
shows that an oligo(Aib) 310 helix carrying an N-terminal l-
amino acid residue (specifically l-valine (l-Val), l-alanine (l-
Ala) or l-phenylalanine (l-Phe)) adopts left-handed (M)
helicity. Corresponding 310 helices carrying an N-terminal a-
methylated (quaternary) amino acid such as l-a-methylvaline
(l-aMv) or l-isovaline (l-Iva) conversely adopt the expected
right-handed (P) helicity.
Achiral tetramers of Aib were made as their N-terminal
azide and C-terminal tert-butyl ester, N3Aib4OtBu (1),[10] and
coupled at their C terminus with either GlyNH2 to give 2 or
with enantiomerically enriched mono-13C-labeled (R)-Aib*[19]
to give 3 (Scheme 1). After reduction of the N-terminal azide,
ligation of 2 or 3 with a selection of Cbz-protected l-amino
acids gave the sets of compounds 4 and 7 shown in Scheme 1.
The l-a-amino acids employed were the tertiary a-amino
acids l-Val (a), l-Phe (b), and l-Ala (c) as well as the
quaternary a-amino acids l-aMv (d) and l-Iva (e).
[*] R. A. Brown, Dr. T. Marcelli, Dr. M. De Poli, Dr. J. Solꢀ,
Prof. J. Clayden
School of Chemistry, University of Manchester
Oxford Road, Manchester M13 9PL (United Kingdom)
E-mail: clayden@man.ac.uk
Dr. T. Marcelli
Dipartimento di Chimica, Materiali e Ingegneria Chimica “Giulio
Natta”, Politecnico di Milano
via Mancinelli 7, 20131 Milano (Italy)
[**] This work was supported by the BBSRC, EPSRC, and ERC. We are
grateful to Prof. Fernando Formaggio, Prof. Claudio Toniolo, Prof.
Tadashi Mori, and Dr. Alison Edwards for helpful discussions, and to
Dean Holt and Romina Wechsel for synthetic assistance. J.C. is the
recipient of a Royal Society Wolfson Research Merit award. T.M.
acknowledges the MIUR (Rientro dei Cervelli 2008) and the
Politecnico di Milano for financial support. We are indebted to
CILEA for the generous allocation of computer time.
Scheme 1. Peptides used in the study. Reagents and conditions:
a) CF3CO2H, CH2Cl2, 24 h; b) Ac2O, 1208C, 3 h then HGlyNH2·HCl,
Et3N, MeCN, D, 3 days; c) as for (b) but with HAib*OMe·HCl; d) H2,
10% Pd/C, MeOH, 24 h; e) CbzXxxOH, PyBOP, iPr2NEt, CH2Cl2, 24 h
for a,b or CbzXxxF, iPr2NEt, MeCN, 72 h for c–e; f) H2, 10% Pd/C,
EtOH, AcOH, 24 h then AcCl, py, CH2Cl2/DMF (1:1), 24 h; g) H2, 10%
Pd/C, EtOH, AcOH, 48 h then pBrBzCl, iPr2NEt, CH2Cl2, 48 h.
Me*=13CH3. Gly=glycine, Cbz=benzyloxycarbonyl, PyBOP=1-benzo-
triazolyloxytris(pyrrolidino)phosphonium hexafluorophosphate,
py=pyridine.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201107583.
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CD spectroscopy gives reliable information on the screw
sense of helical structures,[20] and in helical peptides the sign
and magnitude of absorption bands associated with the n–p*
and p–p* transitions of the amide carbonyl groups report on
the nature and absolute orientation of the helicity.[21] To
minimize interference from transitions owing to aromatic
chromophores associated directly with the chiral amino acid,
peptides 4a, b, and d were deprotected and converted into
their N-acetyl derivatives 5. For comparison with reported
spectra,[9,22] they were also converted into their N-p-
bromobenzamide derivatives 6. CD spectra of 5 were
acquired at 208C in methanol (Figure 1) and in 2,2,2-
trifluoroethanol.
Figure 2. Sections of 13C NMR spectra (CD3OD, 238C) of XxxAib4-
Aib*OMe 7a,b,d and 8a,d.
group (i.e. made from (R)-Aib* of ca. 40% ee).[19] With a
tertiary l-amino acid at the N terminus (7a,b, or 8a) the label
appears predominantly in the more upfield member of the
pair of diastereotopic signals; with a quaternary l-amino acid
at the N terminus (7d, 8d) the label appears predominantly in
the more downfield member of the pair of diastereotopic
signals.[24]
Aib is the most powerful known stabilizer of b turns[25]
and specifically stabilizes a type I or type III b turn at
positions i + 1 and i + 2 and a type II b turn at position i +
2.[26] The N terminus of peptides such as 5 is therefore
expected to adopt either a type II or a type III b turn
conformation[27] with the chiral l-amino acid and Aib located
at the i + 1 and i + 2 positions, respectively (Figure 3). The
Figure 1. CD spectra of Ac-l-XxxAib4GlyNH2 5a, 5b, and 5d in MeOH.
The three compounds 5a, b, and d showed bands with
characteristics of 310 helices with maxima at 208 nm accom-
panied by shoulders at 220 nm,[9] and comparison of the form
of the CD spectra of the peptides 5a,b bearing tertiary l-
amino acid residues with that of peptide 5d bearing a
quaternary l-amino acid residue suggested that the sense of
helicity is opposite for the two classes.[23]
Final confirmation that l-Val-capped Aib oligomers and
l-aMv-capped Aib oligomers adopt opposite helical confor-
mations was provided by 13C NMR spectroscopy. The two
methyl groups of each Aib residue in an Aibn helix, if they are
distant from any chiral residue, are in magnetically inequiva-
lent environments owing to the chirality of the helix,[7] and the
environments of the diastereotopic methyl groups switch
when the absolute sense of helicity switches. By incorporating
in a position remote from the chiral N terminus an Aib
residue differentially and enantioselectively labeled with 13C
in each of its enantiotopic methyl groups, it is therefore
possible to compare the absolute sense of helicity of different
helical peptides by observing whether the label appears
mainly in the upfield or downfield member of the pair of
diastereotopic signals in the 13C NMR spectrum. We have
previously used such a method to report the controlled
inversion of screw sense in an Aib oligomer.[17] Figure 2 shows
portions of the 13C NMR spectra at 238C in methanol of such
labeled peptides 7a,b,d and 8a,d, each carrying a C-terminal
Aib*OMe residue with a 13C label located approximately
70% in the pro-R methyl group and 30% in the pro-S methyl
Figure 3. a) Ideal torsions for type II and III peptide b turns. b) Opti-
mized 310 helical geometries for peptide 5 in a left-(M) and right-
handed (P) helical conformation. Methyl hydrogen atoms are omitted
for clarity.
direction of twist in each of these b turns is opposite
(Figure 3a), so it seemed possible that the opposite helicities
evident in peptides capped by tertiary or quaternary l-amino
acids could arise from a difference in the relative stability of
the two types of turn containing the two classes of amino
acids.
To explore this hypothesis, we used density functional
theory (DFT) calculations to study the conformational
preferences of the peptides.[28] For compounds 5a and 5d, a
left-handed (M) helix with a type II turn at the N terminus
and a right-handed (P) helix with a type III turn at the
N terminus were found to have the lowest energy, differing by
less than 2.4 kJmolÀ1 (Figure 3b). M helices containing N-
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terminal type III turns and P helices containing N-terminal
type II turns were found to be less stable by 6.8–15.9 kJmolÀ1.
These calculated energy differences are, however, too small to
allow a reliable prediction of helical preferences. To this end,
we used time-dependent DFT (TD-DFT) calculations to
construct CD profiles for the four optimized conformations of
5a and 5d. Overlaid calculated and experimental CD spectra
are shown in Figure 4. TD-DFT calculations yield very similar
leads us to the general conclusion that peptides W-Xxx-Aibn-
Y (where W is a carbamate or amide protecting group and Y
is a C-terminal ester or amide) adopt left-handed helicity if
Xxx is a tertiary l-amino acid and right-handed helicity if Xxx
is a quaternary l-amino acid (see Figure 3b, with R = H and
R = Me, respectively).[29]
A reported study of absolute helicity in Aib oligomers
bearing an N-terminal chiral amino acid[9] had also employed
CD spectroscopy, but had come to the conclusion that both l-
Val and l-aMv induce the same, right-handed helicity.
Toniolo et al. had proposed that N-p-bromobenzamide
(pBrBz) protection allows the sense of helicity of an Aibn
chain to be correlated with the sign of the Cotton effect
arising from the pBrBz chromophore in the 210–300 nm
region of the spectrum.[22] However, we find that the CD
spectra of the pBrBz-protected peptides 6a,b,d and 8a,d all
show the same Cotton effect (Figure 5 and the Supporting
Figure 5. CD spectra of peptides pBrBz-l-XxxAib4GlyNH2 6a,b,d.
Information) whether they carry N-terminal tertiary or
quaternary l-amino acids, despite the clear switch in helicity
between 5a and 5d shown by CD spectroscopy (Figure 4) and
between 8a and 8d shown by 13C NMR spectroscopy
(Figure 2).[30] This mismatch indicates that the CD spectrum
of pBrBz derivatives is not an indicator of helicity when the
adjacent amino acid is chiral, presumably because its chro-
mophore is influenced more strongly by the configuration of
the adjacent chiral amino acid (which is here l in all cases)
than by the overall helicity of the peptide.[31]
Support for this explanation of the unreliability of an N-
terminal pBrBz chromophore as a reporter of helicity came
from TD-DFT calculations on peptides 6a and 6d. In this
case, we explored only the two most stable arrangements
(left-handed helix with type II turn and right-handed helix
with type III turn). We found the small torsional angle
between the phenyl ring and the carbonyl group of the p-
bromobenzamide chromophore (c) to be the key factor
governing the appearance of the CD spectrum in the 230–
280 nm region (illustrated for 6a in Figure 6).[32] For peptides
containing an N-terminal amino acid, the preference for a
certain value of c originates directly from the local stereo-
genic center in the surroundings of the pBrBz chromophore
and not from the overall screw sense of the helix. For this
Figure 4. Experimental and calculated CD spectra for peptides 5a and
5d as left-handed (b) and right-handed (g) helices with type II or
type III turns at their N termini.
results for both compounds, indicating that replacement of
the a-hydrogen atom of l-Val with the a-methyl group of l-
aMv has little effect on the chiroptical properties of the
peptide. Likewise the geometry of the first turn of the helix
has a minor impact on the overall shape of the predicted
spectra, with CD curves for type II and type III turns being
similar. On the other hand, the calculations predict that P and
M helices give rise to opposite Cotton effects, thus pinpoint-
ing the overall sense of helicity as the main factor determining
the CD profile of compounds 5a and 5d. The comparison
between the calculated and measured CD spectra shows an
excellent level of agreement between theory and experiment,
which strongly suggests that the l-Val residue of peptide 5a
induces it to adopt left-handed (M) helicity, while the l-aMv
induces peptide 5d to adopt right-handed (P) helicity.
Correlation with the CD and 13C NMR spectra (Figure 1
and Figure 2) of Aib oligomers bearing other amino acids
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reason, the sense of helicity cannot be assigned based on CD
bands associated with this chromophore.[33]
We conclude that C-a-methylation of an N-terminal l-
amino acid is sufficient to cause a switch in the sense of
helicity of an oligomer of achiral amino acids from left to
right, probably by altering the conformational preference of
the N-terminal b turn from type II to type III. We find that
previous reports that an N-terminal tertiary l-amino acid
induces right-handed helicity in an Aib oligomer to be
erroneous, owing to the unreliability of an N-terminal pBrBz
chromophore as an indicator of screw-sense preference when
it lies adjacent to a chiral amino acid. In the light of recent
reports of the ongoing use of the N-pBrBz chromophore as a
marker of helix screw sense,[34] it is worth pointing out that
there is no reason to doubt its effectiveness as a reporter when
it lies remote from the chiral amino acid.
Absolute helicity induced in an achiral peptide chain by a
single N-terminal l-amino acid may evidently be opposite to
that induced in a peptide in which l-amino acids are
abundant, and we are currently exploring the role of
variations of the nature, number, and position of chiral
residues located close to the N terminus of peptides built
largely from achiral residues in determining the sense and
magnitude of the overall helical preference of the chain.
Received: October 27, 2011
Published online: January 3, 2012
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Keywords: circular dichroism · conformation analysis ·
foldamers · helical structures · peptides
.
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has been observed in related structures in the crystalline state
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[28] See the Supporting Information for calculated energies
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À22 nm, which is the difference between calculated (264 nm)
and experimental (242 nm) maximum UV absorption of this
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the Supporting Information.
[24] The magnitude of the anisochronicity also provides a measure of
relative helical conformational preference: see Ref. [8],[10] and
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