Conformational Switching in Heterochiral α,β2,3-Hybrid Peptides in Response to Solvent Polarity

Article abstract of DOI:10.1002/ejoc.201500534

The ability of α,β^2,3-hybrid peptides with a heterochiral backbone to exist in a helical, extended, or partially folded state depending on the solvation conditions employed was investigated. The preference was found to be directly dictated by C_α-C_β torsions in the β-residues. α,β-Hybrid peptides with a heterochiral backbone show the ability to exist in a helical, extended, or partially folded conformation depending on the solvation conditions employed.

Full text of DOI:10.1002/ejoc.201500534

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201500534
Conformational Switching in Heterochiral α,β2,3-Hybrid Peptides in Response
to Solvent Polarity
Dhayalan Balamurugan[a] and Kannoth M. Muraleedharan*[a]
Keywords: Conformation analysis / Foldamers / Peptides / Amino acids
The ability of α,β2,3-hybrid peptides with a heterochiral back-
bone to exist in a helical, extended, or partially folded state
depending on the solvation conditions employed was investi-
gated. The preference was found to be directly dictated by
Cα–Cβ torsions in the β-residues.
sions in response to intramolecular hydrogen-bonding pos-
sibilities.[8] It was also possible to initiate sequential un-
winding of helical turns in their homologous (α,β)nα oligo-
mers by increasing solvent polarity.[9] In fact, the stereo-
chemistry and substitution pattern at Cα and Cβ restrict the
rotamer preference to either gauche or anti, which in turn
translates into a helical or extended conformation in such
systems; such a preference is tunable by adjusting the chem-
ical environment or temperature. As the next step, we chose
to alter the torsions around specific residues by introducing
the opposite stereoisomer of the β2,3-residue at the respec-
tive locations (Figure 1). Excitingly, this study not only led
to molecules that respond to changes in their chemical envi-
ronment by adopting different but well-defined conforma-
tions, but it also gave an understanding on the key back-
bone torsions that dictate these preferences. Peptides 1–3
used in this study were prepared by HATU {1-[bis(dimeth-
ylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-
oxide hexafluorophosphate} mediated solution-phase pept-
ide synthesis, and structure elucidation was done by using a
Introduction
The requirement of a specific molecular conformation is
central to every protein function, and its dependence on
accessible φ/ψ torsions and secondary interaction possibil-
ities clearly show that the parameters that regulate the fold-
ing phenomena are multifaceted. The design of synthetic
models of peptides and proteins with comparable confor-
mations and properties has been a fascination for research-
ers working in this field.[1] Given that a fine balance be-
tween entropic and enthalpic factors is necessary to obtain
a well-defined conformation, especially in solution, there
have been intense efforts since the early 1990s to use residue
preorganization,[2] metal coordination,[3] and cross-link-
ing[4] as strategies to create conformationally unique mo-
lecular systems. After early work from the laboratories of
Seebach[5] and Gellman,[6] this field has grown tremen-
dously during the last couple of decades, and the group
of molecules that can adopt well-defined conformations in
solution are now collectively known as “foldamers”.[2,7] The
development of small oligomeric systems capable of switch-
ing from one well-defined conformational state to another
in response to variations in the chemical environment is
equally important. Apart from giving a closer look at sol-
vation effects on backbone torsions, these oligomeric sys-
tems could find application in the design of stimuli-respon-
sive functional molecules/materials. During our studies on
1
combination of H NMR, 13C NMR, COSY, TOCSY, and
ROESY spectroscopy and HRMS. They can be considered
the conformational characteristics of a new group of α,β2,3
-
peptides, we realized that creation of such “switchable fold-
amers” is indeed possible and our observations are delin-
eated below.
Previously, we reported a group of α,β2,3-hybrid peptides
with (α,β)n composition that can adjust their Cα–Cβ tor-
[a] Department of Chemistry, Indian Institute of Technology
Madras,
Chennai 600036, India
E-mail: mkm@iitm.ac.in
http://chem.iitm.ac.in/faculty/muraleedharan/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500534.
Figure 1. Chemical structures of heterochiral α,β2,3-hybrid peptides
1–3 chosen for this study.
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D. Balamurugan, K. M. Muraleedharan
SHORT COMMUNICATION
as the simplest members of α,β2,3-hybrids with alternation Table 1. Selected backbone torsions from the X-ray structures of
peptide 1 crystallized from CHCl3 and 2-propanol; local conforma-
of chirality in β-residues.
tion around individual residues is evident from the θ values.
Results and Discussion
The solvent-shielded nature of the internal NHs in 1 was
clear from [D6]DMSO titration experiments [ΔδNH = 0.16–
0.24 ppm for NH(2), NH(3) and NH(4); Figure S2, Sup-
porting Information]. Although the splitting pattern of the
CβH signals (1H NMR in CDCl3) was expected to give in-
Solvent
Conformer
Residue
φ [°]
θ [°]
ψ [°]
formation on its folding preference, heavy overlap of the
2CβH and 4CβH signals made the analysis difficult; its
ROESY spectrum was also less useful because of signal
overlap. We were, however, successful in getting X-ray qual-
ity crystals of this peptide by slow evaporation of its chloro-
form solution, and diffraction analysis showed it as having
a left-handed 11-helical conformation (Figure 2, a). This
was facilitated by gauche conformation of the 2Cβ unit with
CHCl3
CHCl3
iPrOH
iPrOH
iPrOH
iPrOH
–
–
I
I
II
II
2
4
2
4
2
4
111.7
–129.1
103.6
–94.6
108.9
–79.3
177.6
175.7
168.7
–173.8 –121.8
160.1 130.6
70.6
130.5
120.6
113.3
–101.3
were θ = –173.8 and 160.1°. Selected backbone torsions in
these structures are presented in Table 1. The arrangement
if viewed along b axis is shown in Figure 2 (b). The
hydrogen-bonding distances and relevant angles in these
systems are included in Table 2.
4
θ = –79.3° (Table 1). Interestingly its Cβ unit is antiper-
iplanar with θ ≈ 177.6°, which suggests that stereochemical
differences at that location do not adversely affect the fold-
ing ability in CHCl3. Dispersion of signals was very good
1
if the H NMR spectrum was recorded in [D6]DMSO. The
second and fourth CβHs appeared as apparent triplets with
J values of 9.0 and 9.5 Hz, respectively, which indicated
antiperiplanar arrangement in these residues. This was fur-
ther supported by the ROESY spectrum recorded in the
same solvent, which had NOEs only from the adjacent resi-
dues (i,i+1 type). These data clearly show the ability of
peptide 1 to choose either a fully extended or a fully helical
conformation depending on whether the medium is
hydrogen bonding or not.
Table 2. Hydrogen-bonding distances and angles observed in the
crystal structures of peptide 1.
Condition
CHCl3
Type
H···O [Å] ЄN–H···O [°]
Boc-C=O···NH(3) Intra
CO(1)···NH(4)
2.192
2.162
2.212
2.266
2.153
161.9
164.1
145.7
144.4
155.7
iPrOH
IICO(1)···INH(1) Inter
IICO(3)···INH(3)
ICO(3)···IINH(3)
To determine whether the nature of the solvent could
Although the resonance dispersion of 1 in CDCl3 was
dictate the folding profile and packing in the solid state, poor at room temperature, a noticeable improvement was
peptide 1 was subsequently crystallized from 2-propanol by observed upon performing the experiment at 313 K. Pleas-
slow evaporation. As anticipated on the basis of hydrogen- ingly, the helicity remained unperturbed, as indicated by a
3
bonding effects from 2-propanol, a strand-like conforma- clear apparent doublet for 2CβH with JC H,C H and
β
α
tion was observed in this case (Figure 2, b). Closer analysis 3JC H,NH values of 4.8 and 9.6 Hz, respectively (Table 3).
β
of the lattice revealed the existence of a pair of conforma- The C-terminal β-residue at the same time preferred an anti
3
3
tional isomers (I and II, Figure 2, b) that formed parallel conformation with JC H,C H = JC H,NH ≈ 8.8 Hz. A step-
β
α
β
β-sheet-like structures stabilized by ICO(3)···IINH(3) wise increase in the temperature to 328 K led to little
hydrogen bonding through the bottom face of I and two change in the position of the signals or the splitting pattern
such secondary interactions [IICO(1)···INH(1) and (Figure 3, a). The experiments were then repeated with
IICO(3)···INH(3)] through the top. Remarkably, the second [D8]toluene to access higher temperatures. As evident from
and fourth CβHs of conformer I chose to have a near anti- the data presented in Table 3, the spectral characteristics
periplanar arrangement with θ = 175.7 and 168.7°, respec- did not show much variation till 368 K, and then they were
tively, whereas the corresponding values for conformer II comparable to those obtained from CDCl3, which further
Figure 2. X-ray crystallographic structures of 1 based on diffraction analyses of its crystals grown from (a) chloroform and (b) 2-prop-
anol.[10] Nonrelevant hydrogen atoms and the co-crystallized solvent molecule are omitted for clarity.
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Conformational Switching in Heterochiral α,β2,3-Hybrid Peptides
confirmed its conformational integrity and stability. Given follow the transition from one conformation to another
that all CβH signals were well dispersed in [D8]toluene (Fig- upon changing the polarity of the chemical environment.
1
ure 3, b), we could obtain the crucial NOE information that Towards this, the H NMR spectra of 1 in CDCl3 after in-
was not possible from CDCl3 because of signal overlap. The cremental additions of [D6]DMSO were recorded (0–100%
characteristic 2CβHǞ4NH NOE indicative of an 11-helical [D6]DMSO), and changes in the signal positions and their
conformation from the experiment performed in a [D8]tolu- splitting patterns were systematically analyzed. A signifi-
ene/CDCl3 (4:1) mixture is presented in Figure 3 (d). Inter- cant downfield shift in all NH signals along with separation
2
4
estingly, the behavior in CD3CN was slightly different (Fig- of the CβH and CβH signals was seen on using 20% [D6]-
ure 3, c, see also Figure S5 and Table S2 in the Supporting DMSO (Figure 4). Whereas the 2CβH signal was broad,
4
4
Information). The CβH signal in this case appeared as an likely because of rotamer equilibria, the CβH signal came
apparent triplet with equal J values of 9.5 Hz in the tem- as an apparent triplet in support of an anti conformation
4
perature range of 298 to 348 K and showing anti conforma- across Cα–Cβ under this condition. A further increase in
tional preference around this residue as in previous cases. the [D6]DMSO content was found to affect the signals of
2
At the same time, broad appearance of the 2CβH signal NH(1), NH(2), NH(3), and CβH to a greater extent than
4
made its J value assessment difficult for experiments per- the signals of NH(4) and CβH, which suggests enhanced
formed in the temperature range of 298 to 318 K. Fortu- conformational transitions in the first three residues. A
2
nately, this signal was well resolved with a dd pattern with broad CβH signal in experiments involving 50–80% [D6]-
J values of 7.5 and 9.5 Hz for experiments done at 328 and DMSO and its emergence as a separate apparent triplet in
2
348 K. The intermediate J value for CβH and a consistent 100% [D6]DMSO, if correlated with continuous downfield
3
and large JC H,CαH for 4CβH under this condition sug- shifts of the signals of NH(1), NH(2), and NH(3), suggest
β
2
gested a considerable degree of rotational transitions in the that the Cβ–Cα torsion equilibrates more towards the anti
first half of the molecule with minimum disturbance in the form upon increasing solvent polarity. This happens in re-
C terminus.
sponse to enhanced hydrogen bonding with the solvent in
the unfolded state.
1
Table 3. Results from a temperature-dependent H NMR study of
tetrapeptide 1 in CDCl3 and [D8]toluene; CβH splitting pattern [ap-
parent triplet: app. t, or doublet of doublets: dd] gives a direct pic-
ture of Cα–Cβ torsion in these systems.
T [K]
CDCl3
T [K] [D8]Toluene
4CβH
(app t)
J1 = J2
[Hz]
2CβH (dd)
4CβH
(app. t)
J1 = J2
2CβH (dd)
J1
J2
J1
J2 [Hz]
[Hz] [Hz]
[Hz]
[Hz]
[a]
[a]
[a]
[a]
[a]
298
313
328
–
–
–
298
318
328
368
8.0
8.0
8.0
8.0
–
–
8.8
8.8
4.8
4.8
9.6
9.6
5.0
5.5
5.5
9.0
9.0
8.5
[a] J values could not be deciphered in these cases owing to signal
3
3
overlap/poor splitting pattern (J1 = J
; J2 = JC H,NH).
CβH,CαH
β
Figure 4. Relevant regions of the 1H NMR spectra of 1 in different
proportions of [D6]DMSO and CDCl3; percentage of [D6]DMSO
is indicated on the left-hand side. Two apparent triplets correspond-
ing to the second and fourth CβH (3J ≈ 9.0 Hz) in the dotted box
indicate a completely extended conformation for 1.
Peptide 1, in the folded state, has two intramolecular
hydrogen-bonding interactions (i,i+3 C=O···HN). Its un-
folding through gauche to anti shift across 2Cβ–Cα with sol-
vent polarity shows the interplay and compromise between
entropy and enthalpy changes as these intramolecular sec-
ondary interactions give way to intermolecular ones. Al-
though realization of this in a segment as short as a tetra-
peptide itself is exciting, we moved ahead to witness similar
conformational preferences in its higher oligomers. On the
basis of the structure of 1, we anticipated that stereochemi-
cal inversion at the C-terminal β-residue would have only a
minimum influence on the stability of the helix. Hence, only
Figure 3. Relevant regions of the variable-temperature (VT) NMR
spectra of 1 in different solvents showing the nature of the CβH
signals: (a) CDCl3, (b) [D8]toluene, and (c) CD3CN (complete VT
NMR spectra are given in Figures S3–S5, Supporting Infor-
mation); (d) expanded region of the ROESY spectrum of 1 in
[D8]toluene/CDCl3 (4:1) showing the long-range NOEs.
Given that solvation effects are crucial in the selection of peptides 2 and 3 were chosen for detailed analysis. Reso-
conformation in the solid and solution states, we set out to nance dispersion in their 1H NMR spectra was good, which
Eur. J. Org. Chem. 2015, 5321–5325
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D. Balamurugan, K. M. Muraleedharan
SHORT COMMUNICATION
made signal assignment easy. The 2CβH signals of these
peptides were broad doublets in support of specific folding
around this residue. Surprisingly, both 4CβH and 6CβH gave
3
apparent triplets with equal J values (3JC H,C H = JC H,NH
= 8.0–8.5 Hz) showing preference for antiβconformation ac-
ross the associated Cα–Cβ bonds. Overall, this implied that
the 11-helical structure exists only in the first half of the
molecule, which is followed by an extended strand-like con-
formation from the fourth residue onwards, and this makes
it a unique hybrid of helix and strand! In strong support of
this, the ROESY (500 MHz, CDCl3) spectra of these pept-
ides showed only one nonsequential NOE corresponding to
the 2CβHǞ4NH interaction (Figure 5, c,d). The absence of
other long-range NOEs once again suggested that the re-
maining part of the molecule adopts an extended confor-
mation.[9]
α
β
Figure 6. Solvent-induced conformational transition in hexapept-
ides 2 (a) and 3 (b) in varying proportions of CDCl3 and [D6]-
DMSO; appearance of 2CβH as an apparent doublet in CDCl3 and
the change in its splitting pattern with increasing amount of [D6]-
DMSO are shown.
There have been a large number of efforts in the past to
closely monitor conformational transitions by using peptide
sequences designed on the basis of either relevant segments
from proteins or rational means. Temperature, pH, concen-
tration, ionic strength, solvents, and pressure are some of
the variables that were found to be influential in bringing
about transition from one conformational state to an-
other.[11] Peptides with appropriate alternation of polar and
nonpolar residues are known to adopt specific conforma-
tions owing to their tendency towards an amphipathic ar-
rangement and have been widely used for accessing different
conformations.[12] In line with this, Dado and Gellman ele-
gantly used methionine side-chain oxidation as a tool to
fine-tune polarity characteristics and were successful in
identifying a redox-switchable 18-residue peptide.[13] Studies
Figure 5. (a,b) Chemical structures of α,β-peptides 2 and 3. Dotted
arrow lines in the chemical structure indicate nonsequential NOEs
in the ROESY (CDCl3) spectrum. Hydrogen-bonding interactions
proposed on the basis of the NMR spectroscopy data are indicated
with solid arrow lines. Relevant regions in the ROESY (CDCl3) of
(c) 2 and (d) 3.
Their response to solvent polarity was also remarkable, on the effect of N-terminal hydrophobicity on the α-helix
and 1H NMR spectral changes could be directly used to to β-sheet transition in α-peptides,[14] redox-switching of the
follow the transition from a partially folded conformation Ac-SIRKLEYEIEELRLRIG-NH2 peptide between ex-
to a fully extended conformation. Initial solvent titration tended and helical conformations by making use of its
experiments revealed that the signals of NH(1), NH(3), and differential affinity towards CuII/CuI ions,[15] photoswitch-
NH(5) of 2 and 3 undergo larger downfield shifts than the ing of peptide conformation with a built-in azobenzene
signals of NH(2), NH(4), and NH(6) on incremental ad- unit,[16] chain-length-dependent 10- or 14-helical prefer-
ditions of [D6]DMSO (up to 30% v/v in CDCl3; Figures S6, ences in trans-2-aminocyclohexane carboxylic acid oligo-
Supporting Information). More than their solvent-exposed mer,[17] solvent-driven α- and 310-helical preferences of an
nature, we believe that [D6]DMSO induces some degree of N-acylated homoheptapeptide isopropylamide based on l-
unfolding, and this could be the reason why NH(3), which α-methylvaline in the crystalline state,[18] partially unwound
is normally associated with intramolecular i,i+3 hydrogen- helical structure in hexameric oligourea containing a sele-
bonding interactions, suffers a greater shift. The signal of nourea moiety proximate to the positive pole,[19] partially
2CβH continued to be broad in the [D6]DMSO concentra- unwound helical structure of a four residue γ-peptide ana-
tion range of 0 to 25% (Figure 6). In the case of 3, the logue having a carbamate–urea hybrid sequence,[20] and zig-
2
4
6
signal of CβH merged with those of CβH and CβH at zag tap-like conformation stabilized by α- and γ-turns in a
50% [D6]DMSO, and on increasing the concentration fur- hybrid octapeptide of leucine with a 8-amino-2-quinol-
ther (75% [D6]DMSO) we could see two distinct apparent inecarboxylic acid derivative[21] are some selected examples
triplets in a 1:2 ratio; for 2, all these signals were in the showing the active interest in understanding and manipulat-
same place with significant signal overlap. These observa- ing folding preferences of peptides and peptide mimetics.
tions tend to indicate that the 11-helical segment in the N- Fülöp et al. have previously shown that oligomers based on
terminal region of 2 and 3 unwinds at a lower [D6]DMSO cis-2-aminocyclopentanecarboxylic acid (cis-ACPC) have a
concentration than that required for 1.
tendency to adopt an extended conformation, unlike their
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Conformational Switching in Heterochiral α,β2,3-Hybrid Peptides
analogues based on trans-ACPC.[22] The idea of chirality
alternation has also been experimented by the Fülöp group
by using some selected cis- and trans-ACPC oligomers.
Among these, heterochiral cis-ACPC peptides were found
to assume a H10/12 helical structure. At the same time, the
heterochiral trans-ACPC oligomer existed as a polar
strand.[23] As mentioned before, we recently reported the
sequential unwinding of helical turns in peptides with
(α,β)nα composition through incremental changes in solvent
polarity/temperature.[9] The present work is in continuation
of our efforts in this direction and shows that heterochiral
sequences of this class of peptides are good candidates for
accessing partially folded conformations. The ability of
peptide 1 to exist in either a helical or extended state de-
pending on the chemical environment points towards the
potential use of such hybrid peptides in the design of stim-
uli-responsive materials.
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Conclusions
The ability of proteins to shift from one specific confor-
mation to another in response to biological triggering
events is responsible for the high degree of regulation in
every cellular function. Simulation of such transitions by
using small oligomers is an extremely important subject ow-
ing to its direct application in the design of new functional
systems. Such studies are also of special significance, as they
can shine light onto the intricacies of protein folding.
Herein, we presented a group of α,β2,3-peptides with a het-
erochiral backbone; these peptides not only assume specific
conformations depending on the solvent but also respond
to a change in polarity by shifting from one conformation
to another. The helical and extended structural preferences
of tetrapeptide 1 in CDCl3 and [D6]DMSO, respectively,
was retained in its crystals grown from solvents of compar-
able polarities. Using a similar design strategy, we accessed
two hexapeptides capable of adopting a half helix–half
strand structure. Realization of a combination of two ex-
treme conformations in a segment as short as a hexapeptide
is remarkable and can be used as a model system to under-
stand the fine balance between enthalpic and entropic fac-
tors during conformation selection.
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Acknowledgments
Financial support of this work by the Department of Science and
Technology (DST), New Delhi (grant number SR/S1/OC-13/2007),
and the Departmental instrumentation facility by DST (FIST) are
gratefully acknowledged. The authors thank Mr. V. Ramkumar,
Department of Chemistry for X-ray diffraction analysis. D. Bala-
murugan thanks DST and the Indian Institute of Technology Ma-
dras (IITM) for a research fellowship.
[1] a) L. M. Johnson, D. E. Mortenson, H. G. Yun, W. S. Horne,
Received: April 27, 2015
Published Online: July 20, 2015
T. J. Ketas, M. Lu, J. P. Moore, S. H. Gellman, J. Am. Chem.
Eur. J. Org. Chem. 2015, 5321–5325
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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