Measuring screw-sense preference in a helical oligomer by comparison of 13C NMR signal separation at slow and fast exchange

Article abstract of DOI:10.1021/ja1097034

While an unequal population of rapidly interconverting left- and right-handed conformers of a helical oligomer can be detected by circular dichroism, precise quantification of a conformer ratio has not previously been achieved. We demonstrate, using a set of labeled peptide analogues, that simple analysis of peak separation in their ¹³C NMR spectra at slow and fast exchange allows an accurate value for the ratio of helical conformers to be obtained. The method reports the ratio of conformers at the site of the label and can therefore be used to investigate local variations in helical conformational control.

Full text of DOI:10.1021/ja1097034

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Measuring Screw-Sense Preference in a Helical Oligomer by
Comparison of 13C NMR Signal Separation at Slow and Fast Exchange
Jordi Solꢀa, Gareth A. Morris, and Jonathan Clayden*
School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, U.K.
S Supporting Information
b
ABSTRACT: While an unequal population of rapidly inter-
converting left- and right-handed conformers of a helical
oligomer can be detected by circular dichroism, precise
quantification of a conformer ratio has not previously been
achieved. We demonstrate, using a set of labeled peptide
analogues, that simple analysis of peak separation in their
13C NMR spectra at slow and fast exchange allows an
accurate value for the ratio of helical conformers to be
obtained. The method reports the ratio of conformers at the
site of the label and can therefore be used to investigate local
variations in helical conformational control.
Figure 1. Diastereotopic groups within helical oligomers and their
NMR signals in the fast and slow exchange rꢁegimes.
iological signal transduction depends on the communication
dichroism can yield data on relative helical preferences by cali-
B
of molecular conformational change, which enables the
bration against known or modeled spectra,21 and when M and P
conformers interconvert slowly, NMR can be used to quantify
the ratios of diastereoisomeric conformers.22
function of membrane-bound receptors and allosteric proteins.1
The challenge of achieving conformational control in synthetic
structures has stimulated the development of foldamers: ex-
tended molecules with well-defined conformational proper-
ties.2,3 Many foldamers are helical, with a preferred helical screw
sense often arising from the presence of chiral monomers within
the oligomeric structure.3
Here we demonstrate that comparison of the 13C NMR
spectra of a set of 13C-labeled helical foldamers in the slow and
fast exchange rꢁegimes provides a simple new method for the
accurate determination of their helical excess. Line-shape analysis
allows both the kinetics and the thermodynamics of screw-sense
inversion to be quantified, and the use of multiple 13C labels
makes possible the measurement of localized screw-sense pre-
ference at specific sites along the helix.
The method depends on the fact that a pair of groups rendered
diastereotopic by virtue of their location within a helical structure
will give rise to anisochronous signals when the screw-sense
inversion of the helix is slow on the time scale of their chemical
shift separation, Δδslow, in Hz (Figure 1). The value of Δδslow is
independent of the ratio of the two screw-sense conformers.
However, when the screw-sense interconversion becomes fast on
the time scale of their chemical shift separation—at higher
temperature for example—a new averaged pair of anisochronous
signals arises with peak separation Δδfast. Δδfast must be 0 if the
M and P conformers of the helix are equally populated, for
example in the absence of a chiral controlling influence. In the
general case, the ratio Δδfast/Δδslow = ([P] - [M])/([P] þ
[M]) = (K - 1)/(K þ 1), where K = [P]/[M] (provided
anisochronicity is temperature-independent). The quantity
Δδfast/Δδslow can be termed “helicity excess” (by analogy with
“enantiomeric excess” = ([R] - [S])/([R] þ [S])).
A preference for helicity should be distinguished from a
preference for a single screw-sense (i.e. M vs P): several classes
of foldamers, including those built from aromatic amides4 and ureas,5
isocyanides,6-8 isocyanates,9-11 and achiral amino acids,12-15 adopt
helical conformations despite being constructed of achiral mono-
mers; they are conformationally helical, but configurationally achiral.
Where screw-sense inversion is slow, as in the polyisocyanides,
kinetic control over the growing helical chain may be used to induce
a preferred orientation.7,8 Where screw-sense inversion is fast, a
thermodynamic conformational influence is required,16 and the
work of Green showed that high levels of thermodynamic control
of helicity can result even from very weak chiral influences;17 mono-
1
2
mers containing a stereogenic center bearing H and H, for
example.10 Screw-sense control has also been achieved by binding
to chiral ligands8,18 or by incorporating a single terminal chiral con-
troller which, if its stereochemistry can be inverted, allows reversible
switching of the helicity of the foldamer,11,19 with the potential to
mimic biological signal transfer mechanisms.20
Whatever mechanism of control is employed, its usefulness
depends on how effectively screw-sense control is achieved; in
other words the quantified preference of the foldamers for M or P
helicity. This figure, which could be termed the “helicity excess”
of the foldamer, has rarely been determined accurately. Circular
Received: November 8, 2010
Published: February 25, 2011
r
2011 American Chemical Society
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Figure 2. 13C-Labeled Aib9 oligomers shown as a P helix with an
N-terminal cap.
In connection with our work on the control and switching of
helical structures built from aminoisobutyric acid (Aib)14,15,19 we
chose to explore and illustrate the utility of this method by
investigating the degree of screw-sense control exerted by an N-
terminal chiral amino acid on a chain of nine Aib residues. Homo-
oligomers of Aib are known to adopt 310 helical conformations in
1
solution,13,23 and both CD and H NMR spectroscopy have
shown that an N-terminal amino acid exerts a measurable, but
unquantified, level of screw-sense control in solution.24
The challenge in determining the helicity excess by our
proposed method is to choose a reporter group with a peak
separation Δδslow which allows both slow and fast rꢁegimes to be
explored at temperatures compatible with solubility of the
oligomer in a suitable solvent. Typical separations of the diaste-
1
reotopic H signals in Aib oligomers and their analogues are
insufficiently large to make slow exchange accessible;14,15 thus,
we turned instead to the 13C signals of selectively 13C-labeled
compounds 1-5 (Figure 2). Dynamic NMR studies of the 13C
spectra of achiral Aib oligomers25-27 and other helices28 have
previously been used to determine kinetic parameters associated
with their screw-sense inversion.
Labeled compounds 1-5 were synthesized by ligating two
N3Aib4Ot-Bu tetramers14 through a doubly 13C-labeled Aib
made by Strecker reaction of acetone-13C2 (details in Supporting
Information [SI]).29 The location of the 13C labels in the middle
of the helix was chosen to avoid specific direct interactions with
the helix termini - especially the chiral controller at the N-
terminus. The labeled methyl groups are of course diastereotopic
as a result of the presence of this chiral controller, irrespective of
helicity, but by locating them at a distance from the controller we
ensure their anisochronicity results only from their interactions
with the helix itself. This synthetic approach gave 1, which was
reduced and coupled with Cbz-L-phenylalanine, Cbz-L-valine,
Cbz-L-R-methylvaline, and Cbz-L-proline to yield peptides 2-5.
Titrations of the peptides 1-5 in CDCl3 with DMSO and
comparison of circular dichroism spectra (see SI) indicated that
2, 3, and 5 adopt preferentially a left-handed (M), and 4 a right-
handed (P) 310 helical conformation in solution.30
13C NMR spectra were acquired for each peptide 1-5 at
temperatures from -60 °C to þ23 °C. Figure 3 shows data
points from the portions of the NMR spectra containing the 13C-
enriched signals of 1-4 in CD3OD and of 2 in CD3CN at a range
of temperatures between -40 and 0 °C. To facilitate line-shape
modeling, data points arising from peaks due to natural abun-
dance 13C signals from the remaining 16 methyl groups of the
oligomers were excised from the traces. For each set of spectra as
a function of temperature, the remaining data points were
subjected to global nonlinear least-squares fitting to a model
assuming doubly degenerate exchange with unequal populations
and Arrhenius kinetics. The fit was performed by iteration on the
Figure 3. Experimental data (gray dots) and fitted spectra (black lines)
for portions of the 13C spectra of labeled CbzXxxAib9Ot-Bu oligomers at
a range of temperatures between 233 and 273K. (a) 1 in CD3OD; (b) 2
CD3OD; (c) 2 in CD3CN; (d) 3 in CD3OD; (e) 4 in CD3OD. Gaps in
the experimental data appear where interfering signals from unenriched
species were excised. Dotted vertical lines for the spectra in methanol
indicate the positions and separations of the peaks at the slow exchange
limit calculated in the fitting process.
limiting chemical shift difference, Δδ, the average chemical shift,
δ, the temperature coefficient dδ/dT of the shift, the natural
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Table 1. Kinetic and Thermodynamic Parameters from 13C NMR Spectra of 1-5 and Corresponding Values for Helical Ratios in
CD3OD
cmpd
Ea/kJ mol-1a
K253K
ΔH253K/kJ mol-1
h.r.253Kb
Δδslow213K/ppm c
Δδfast296K/ppm c
h.r.296Kd
1
35.2 ( 0.1
32.8 ( 1.1
35.5 ( 0.3
1
0
50:50
72:28
67:33
4.36
4.42
4.33
0
50:50
70:30
65:35
60:40f
65:35
76:24
69:31
2
2e
2.56 ( 0.06
2.04 ( 0.01
-1.0 ( 1.0
-1.5 ( 0.2
1.74
1.34
0.91f
1.33
2.31
1.73
3
4
5
34.3 ( 0.2
38.7 ( 0.4
-
1.96 ( 0.02
3.53 ( 0.03
-
-1.0 ( 0.2
-1.5 ( 0.3
-
66:34
78:22
-
4.40
4.40
4.46
a Activation energy for conversion of minor to major helix conformer. b Ratio of major to minor helix conformer calculated from the modeled value of
296K
K253K. c Observed chemical shift difference at the temperature indicated. d Ratio of major to minor helix conformer calculated from the ratio of Δδfast
to Δδslow213K. e In CD3CN. f At 334 K (70 °C).
logarithm ln A of the pre-exponential factor for the major to
minor conversion, the activation energy Ea for that process, the
enthalpy difference ΔH between major and minor partner, and
the entropy difference ΔS between the two. The analytical expre-
ssion for the exchanging spectrum was determined by automated
steady-state solution of the Bloch equations, modified for ex-
Figure 4. Limiting chemical shift differences Δδfast for 13C-labeled Cbz-
change and assuming negligible saturation, using the program
RMv-Aib9Ot-Bu oligomers, with the locations of 13C2 labels within each
molecule identified by differing enrichments.
Mathematica;31 the results obtained were in exact agreement
with those of Gutowsky and Holm32 but cast in a slightly more
convenient form, with a lower highest order of term and, hence,
slightly greater numerical accuracy. In the case of the achiral
peptide, ΔH and ΔS were fixed at zero. Values at 253 K (-20 °C)
for Ea, ΔH, and K, also expressed as a helical ratio (h.r.), are
shown in Table 1.
shown in the last column of the table and are in essentially perfect
agreement with those derived by line-shape modeling if the
effects of the difference in temperature are taken into account.
Increasing the temperature of 2 in MeCN beyond 296 K led to a
further, approximately linear, diminution of the estimated helical ratio
with temperature, dropping from 70:30 at 21 °C to 60:40 at 70 °C.
The values for helicity ratios determined by these methods
apply only at the position of the label. It is to be expected that,
due to a small but finite chance of a helix reversal at each position
in the oligomer, there will be a slow decay of helical preference
moving along the chain away from the helical controller. A
previous study14 estimated a 3.5% loss of helical preference per
Aib residue. To investigate the effect of the position of the 13C
reporter on Δδfast, and hence probe the dependence of the local
helical ratio on the position in the chain, we made two com-
pounds 6 and 7 bearing labels respectively at residues 3, 6, and 9
andatresidues4 and7ofthepeptide(Figure4). Inordertoidentify
the location of the label within each peptide, Aib residues nearest
the N terminus (position 3 or 4) were labeled at 100% abundance,
the next positions (6 and 7) at 50% abundance, and position 9 at
25% abundance. Figure 4 gives values for Δδfast at 23 °C.
A decay of Δδfast as the label was moved along the chain was
clearly evident, except with the label at residue 9, which is too
close to the chain terminus to give reliable information about
helix conformation. Fitting the values of Δδfast (other than that of
residue 9) to an exponential decay14 returned a value for the
fidelity of transmission of helical preference of 0.975, or in other
words a rate of decay of 2.5% per Aib residue. Repeating the study at
30 and 40 °C also gave decay rates of 2.5%. As expected, on
decreasing the temperature, the sets of peaks from the 13Clabelsof6
and 7 coalesced to a single pair of signals with Δδslow = ∼4.30 ppm,
confirming that the change in peak separation (Δδfast) on moving
along the chain is due to a diminishing screw-sense preference and
does not directly result from position in the helix.
The peak separation Δδslow, and indeed the location δ, of the
two signals arising from the labeled diastereotopic methyl groups
at slow exchange in each oligomer was essentially independent of
the terminal residue, changing only with solvent. This result
validates the assumption that the labels experience a local
environment determined solely by the helix which flanks them,
and are not affected by the nature of the helix terminus.
The activation energy for helical inversion, Ea, varied a little
with helix structure and with solvent, and was comparable with (if
slightly lower than) that corresponding to the reported rate of
inversion of an Aib hexamer, octamer, or decamer in CD2Cl2.25,27
Inversion of a 310 helix can occur via a “zipper” mechanism,27 and
with the typical strength of a hydrogen bond being approximately
21 kJ mol-1 33 values in the region of 35 ( 3 kJ mol-1 are
,
consistent with the simultaneous breakage of 1-2 hydrogen
bonds at the transition state for helix inversion.
Consistent with previous reports,25,27 the peaks of 1, devoid of
a chiral residue, coalesced at high temperature to a single signal.
For the rest, raising the temperature led, as expected, to broad-
ening followed by resharpening to a new pair of signals separated
by a new chemical shift difference, Δδfast. The average chemical
shift δ was again independent of the N-terminal residue, consis-
tent with the assumption that chemical shift is not directly
affected by the terminal residue, but only by the local helical
environment.
From the value of K we established that the maximal control of
helix orientation among the residues we studied arose from an
N-terminal R-methylvaline residue, which gave a 78:22 ratio
halfway along the helix. The helical ratio can also be estimated
simply by dividing Δδfast by Δδslow, and acquiring spectra
at -60 C and at þ21 °C gave us sharp signals from which we
obtained these values. The resulting helical ratios at 296 K are
In summary, the method we outline elucidates the substrate-
dependence of helical control with finer detail than is possible by
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circular dichroism, quantifying the screw-sense ratio at a specific
site in a helical structure. The results show that, while Aib
oligomers transmit a helical preference highly effectively, a single
amino acid in fact induces a relatively weak screw-sense pre-
ference, giving rise to a maximum among those studied here of
about 3:1 with R-methylvaline as the controller. The method is in
principle applicable in stereochemically and kinetically compar-
able situations and offers the prospect of the straightforward
determination of helicity excess in a wide range of foldamers.
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’ ASSOCIATED CONTENT
S
Supporting Information. Details of the synthesis and
b
characterization of all peptides, NMR and circular dichroism
spectra, and full details of line-shape modeling. This material is
available free of charge via the Internet at http://pubs.acs.org
’ AUTHOR INFORMATION
Corresponding Author
clayden@man.ac.uk
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’ ACKNOWLEDGMENT
This work was supported by the EPSRC [Grant Reference
E018351]. We thank the Departament d’Innovaciꢁo Universitats i
Empresa de la Generalitat de Catalunya for a postdoctoral fellow-
ship (to JS).
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