Non-classical Helices with cis Carbon–Carbon Double Bonds in the Backbone: Structural Features of α,γ-Hybrid Peptide Foldamers

Article abstract of DOI:10.1002/anie.201602861

The impact of geometrically constrained cis α,β-unsaturated γ-amino acids on the folding of α,γ-hybrid peptides was investigated. Structure analysis in single crystals and in solution revealed that the cis carbon–carbon double bonds can be accommodated into the 12-helix without deviation from the overall helical conformation. The helical structures are stabilized by 4→1 hydrogen bonding in a similar manner to the 12-helices of β-peptides and the 3₁₀helices of α-peptides. These results show that functional cis carbon–carbon double bonds can be accommodated into the backbone of helical peptides.

Full text of DOI:10.1002/anie.201602861

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201602861
German Edition: DOI: 10.1002/ange.201602861
Foldamers
Non-classical Helices with cis Carbon–Carbon Double Bonds in the
Backbone: Structural Features of a,g-Hybrid Peptide Foldamers
Mothukuri Ganesh Kumar, Varsha J. Thombare, Mona M. Katariya, Kuruva Veeresh,
K. Muruga Poopathi Raja, and Hosahudya N. Gopi*
Abstract: The impact of geometrically constrained cis a,b-
unsaturated g-amino acids on the folding of a,g-hybrid
peptides was investigated. Structure analysis in single crystals
and in solution revealed that the cis carbon–carbon double
bonds can be accommodated into the 12-helix without devia-
tion from the overall helical conformation. The helical
structures are stabilized by 4!1 hydrogen bonding in a similar
manner to the 12-helices of b-peptides and the 310 helices of a-
peptides. These results show that functional cis carbon–carbon
double bonds can be accommodated into the backbone of
helical peptides.
from g- and hybrid g-peptides composed of stereochemically
[11]
constrained cyclic g-amino acids. In addition, a variety of g-
[12]
amino acids have been explored in the design of foldamers.
However, little is known about the utilization of geometri-
cally constrained a,b-unsaturated g-amino acids in foldamers
design. Nevertheless, Hofmann and co-workers have pro-
vided a comprehensive overview on the helix types available
to the E- and Z-vinylogous homooligomers using theoretical
[13]
calculations. Recently Maillard and co-workers showed C9
helices from g-peptides composed of thiazole-based amino
[14]
acids, which mimic the Z-vinylogous residues. Grison et al.
and others also reported turn mimetics using Z-vinylogous
[
15]
D
espite backbone conformational freedom, b- and g-
amino acids.
Recently, we demonstrated the design of
peptides, along with hybrid a,b-, a,g-, and b,g-peptide
stable b-hairpins, three-stranded b-sheets, and miniature b-
meander mimetics (Figure 1) through selective incorporation
[1]
sequences, display a variety of distinct helical structures.
Indeed, by carefully controlling the sequence of these non-
natural oligomers, it is possible to mimic protein secondary
structures, and this structural mimicry can be exploited to
[
2]
design inhibitors for protein–protein interactions as well as
[
3]
antimicrobials. In comparison to b-peptides, greater folda-
meric potential is expected from g-residues owing to the
[1d]
presence of three backbone carbon atoms.
Indeed, the
helical folding of g-amino acid oligomers was first examined
[4]
by Rydon using the natural polymer poly-g-d-glutamate. In
early work, Schreiber and co-workers demonstrated the
formation of extended b-sheet and helical structures from
peptides composed of naturally occurring (E)-a,b-unsatu-
Figure 1. A) The unusual planar structure resulting from 1:1 alternating
a-residues and E-vinylogous residues (Boc-Aib-EgPhe-Aib-EgPhe-
[5]
rated g-amino acids. More convincing evidence on the
[17]
OEt). B) A miniature b-meander mimetic consisting of an a,a,g-
[6]
folding of g-peptides came from the groups of Seebach and
[16b]
hybrid peptide (Boc-Leu-Aib-EgPhe-Leu-Aib-EgPhe-OEt).
Aib=2-
[7]
Hanessian, and they independently showed well-defined 14-
aminoisobutyric acid. C green, O red, N blue, H white, vinyl group
orange.
4
2,4
helical organizations from homooligomers of g -, g - and
2
,3,4
g
-amino acids. Furthermore, the foldameric potential of g-
and hybrid g-peptides have been thoroughly investigated
[
8]
[16]
through ab initio theoretical calculations. Balaram et al.
of E-vinylogous residues into hybrid peptides.
Further-
4
3,3
demonstrated the utility of g - and spiro g -amino acids
(
more, we have shown an unusual planar structure from 1:1
[1i,9,10]
gabapentin) in the design of helices.
Recently, Gellman
alternating
a-residues
and
E-vinylogous
By using mild catalytic hydrogenation, we
residues
[
17]
and colleagues have reported a variety of helical structures
(Figure 1).
transformed the unusual planar structure resulting from 1:1
alternating a-residues and E-vinylogous residues and mini-
ature b-meanders into 12 [12-atom H-bond pseudocycle
between C=O(i)···NH(i + 3)] and 10/12 [alternating 10-atom
[
*] M. Ganesh Kumar, V. J. Thombare, M. M. Katariya, K. Veeresh,
Prof. Dr. H. N. Gopi
Department of Chemistry
Indian Institute of Science Education and Research
Dr. Homi Bhabha Road, Pashan, Pune-411008 (India)
E-mail: hn.gopi@iiserpune.ac.in
H-bond pseudocycle and 12-atom H-bond pseudocycle
4
between C=O(i)···NH(i + 3)] a,g -hybrid peptide helices,
[
16b,17]
respectively.
Since E-vinylogous amino acids promote
Prof. Dr. K. M. P. Raja
Department of Physical Chemistry
School of Chemistry, Madurai Kamaraj University, Madurai-625 021
[16]
b-sheet structures in hybrid peptides, we hypothesized that
the geometrical constraints of Z-vinylogous amino acids could
be utilized to design helical structures. Since conjugated
double bonds have been extensively utilized as intermediates
(
India)
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201602861.
[18]
for various chemical transformations,
we anticipate that
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helices with carbon–carbon double bonds may find potential
applications in organic chemistry and chemical biology.
Herein, we report the design, synthesis, and solution and
single-crystal conformation of various a,g-hybrid peptides
(P1–P5) composed of Z-vinylogous residues. Structural
analysis shows that cis double bonds can be accommodated
into an a,g-hybrid 12-helix without deviation from the overall
helix folding.
The sequences of the peptides are given in the Scheme 1.
The design was based on the previously reported, well
4
characterized a,g -hybrid peptide 12-helix P6, which is
4
[19]
composed of alternating a- and g -amino acids. To deter-
mine whether the cis double bond can be accommodated into
4
the helix, we designed P1, in which the g Phe4 in P6 was
4
4
replaced with with Zg Phe (Z-vinylogous g -phenylalanine).
The Z-vinylogous amino acid was synthesized by using the
[20]
Horner–Wadsworth–Emmons (HWE) reaction. Peptide P1
was synthesized through solid-phase synthesis with Fmoc
chemistry. All coupling reactions were carried with 2-(1H-
benzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluoro-
phosphate (HBTU) as coupling agent. The pure peptide
was subjected to crystallization to determine its conforma-
tion.
Diffraction-quality crystals of P1 were obtained through
slow evaporation of the peptide in aqueous methanol
solution, and its X-ray structure is shown in Figure 2.
Strikingly, the structure analysis of P1 reveals that it adopts
a right-handed 12-helix conformation similar to that of model
peptide P6. The 12-helix conformation is stabilized by six
intramolecular H-bonds between i (C=O) and i + 3 (NH)
residues. The H-bond parameters of P1 are tabulated in the
Supporting Information. The backbone conformations of g-
Figure 2. X-ray structures of the a,g-hybrid peptides P1–P5 (Z-vinyl-
ogous residues are shown in yellow and C=C bonds in orange). A
4
superposition of P4 onto the a,g -hybrid peptide P6 is also shown. Top
views are shown below the side views.
residues can be measured by introducing two additional
torsional variables, q and q , along with f and y (Sche-
1
2
[
8b,13b]
[8-
me 1A). Extensive theoretical
investigations suggested that saturated g-residues
prefer to adopt gauche , gauche (g ,g ) conformation along
and experimental
b, 9,10,11a,e, 12e,g]
+
+
+
+
g
b
b
a
C ÀC (q ) and C ÀC (q ) bonds and anticlinal conformations
1
2
g
a
along NÀC (f) and C ÀC’(O) (y) bonds to accommodate
into the helix (q ꢀ q ꢀÆ 608 and fꢀ y ꢀÆ 1208). As with
1
2
4
4
4
peptide P6, the saturated g -amino acids g Leu2 and g Leu6 in
+
+
g
b
b
a
P1 adopted g ,g conformations along C ÀC and C ÀC
g
a
bonds and anticlinal conformation along NÀC and C ÀC’(O)
4
bonds. Interestingly, the unsaturated amino acid Zg Phe4 also
accommodated into the 12-helix, with an inherent cis double
b
a
bond along the C ÀC bond (q ꢀ 08). The torsion angles of
2
4
the Zg Phe4 are listed in the Table 1. Instructively, q and q
1
2
attained values of + 958 and À28, respectively, and f and
y showed the values of À122 88 and À798, respectively. To
determine whether any other Z-vinylogus residues can be
accommodated into the helix, we designed peptides P2 and
4
Scheme 1. A) Local torsion variables of g -residues and Z-vinylogous
residues. B) Sequences of the a,g-hybrid peptides P1–P5, along with
the model a,g -hybrid peptide 12-helix P6.
4
4
4
P3, which contain Zg Val4 and Zg Leu4, respectively, and
7
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Table 1: Dihedral angles of the (Z)-vinylogous residues in P1–P5.
(Figure 2). The excellent backbone correlation between P4
and P6 suggests that Z-vinylogous residues can be accom-
modated into a well folded 12-helix, with a new set of
backbone torsional angles. Strikingly, despite the rigidity of
Peptide
f
q1
q2
y
P1
P2
P3
P4
P5
Average
À1228
958
1068
988
99Æ48
104Æ18
100Æ58
À28
08
À48
À798
À1248
À748
backbone cis double bonds (q ꢀ 08), the 12-helix fold is
2
À1158
À838
facilitated by notable deviations in the neighbored torsion
À119Æ38
À117Æ58
À119Æ48
3Æ18
À1Æ28
0Æ38
À79Æ78
À75Æ28
À78Æ48
angles q and y, which are different from those in other 12-
1
helices (Table 2).
Careful analysis of the local conformations of Z-vinyl-
ogous residues in 12-helices revealed very interesting features
of the carbonyl-conjugated cis carbon-carbon double bonds.
None of the cis double bonds of the Z-vinylogous residues in
the hybrid helices are p-conjugated to the carbonyl groups
since they deviate from planarity (Figure 3C). The local
torsion angles (C -C -C-O = 1038) of Z-vinylogous residues
revealed that the C=C double bonds are almost perpendicular
to the carbonyl group, thus suggesting an absence of
p conjugation (Figure 3C). We envisage that the absence of
p conjugation may have an influence on the reactivity of
double bonds.
synthesized them in a similar manner to P1. The X-ray
structures of P2 and P3 are shown in Figure 2. Both P2 and P3
adopt right-handed 12-helical conformations akin to P1. The
structures are stabilized by six intramolecular H-bonds
between i (CO) and i + 3 (NH) residues. The torsion angles
of the Z-vinylogous residues are listed in the Table 1. Analysis
b
a
4
4
revealed that Zg Val and Zg Leu adopt similar torsion values
4
to those of Zg Phe in P1. Inspired by the successful
accommodation of single cis double bonds into the hybrid
peptide helices P1–P3, we designed P4 and P5, which have 1:1
alternating a-residues and Z-vinylogous residues. The X-ray
structures of P4 and P5 are shown in Figure 2. Remarkably,
peptides P4 and P5 adopt right-handed 12-helical conforma-
tions in single crystals. In sharp contrast to the unusual planar
conformation of hybrid tetrapeptides composed of 1:1 alter-
[17]
nating a-residues and E-vinylogous residues (Figure 1),
hybrid peptides with 1:1 alternating a-residues and Z-vinyl-
ogous residues adopt a 12-helix conformation. The average
dihedral angles of Z-vinylogous residues are listed in the
Table 1. The 12-helix conformation in both P4 and P5 is
stabilized by six intramolecular H-bonds between residues
i and i + 3. The 4!1 H-bonding pattern observed in the a,g-
hybrid peptides resembles that of the 12-helix conformation
[
21a]
of b-peptides,
peptides.
which is analogous to the 3 -helix of a-
10
[
21b]
The H-bonding parameters of all the peptides are
tabulated and given in the Supporting Information. Instruc-
tively, structural analysis of P1–P5 revealed that Z-vinylogous
residues attain unique and distinct dihedral angles to accom-
Figure 3. A) Solution conformations of the a,g-hybrid peptides P1 and
P5. B) An overlay of the X-ray and NMR structures of P5. C) The X-ray
structure of peptide P1, illustrating the non-planarity of the C=C and
4
2,4
3,4
3,3
b
a
C O bonds (C -C -C-O=1038) in the Z-vinylogous residues.
=
modate into the helix compared to other g -, g -, g -, g -
2
,3,4
and g -residues, as well as cyclic g-residues. Table 2 shows
a comparison of four torsion angles of Z-vinylogous residues
and other g-residues in various a,g-hybrid 12-helices. Exami-
nation of all the crystal structures (P1–P5) revealed that the
Aib residues display average f and y values of À56 Æ 68 and
À44 Æ 68, respectively. Further, we superimposed the struc-
tures of P4 and P6 to compare their backbone conformations
To gain insight into their solution conformations, we
subjected P1 (a single Z-vinylogous residue) and P5 (three Z-
vinylogous residues) to 2D NMR analysis. Both P1 and P5
1
showed well resolved H NMR spectra in CD OH. The
3
sequence of the amino acids was identified by using
TOCSY and ROESY. Analysis of the ROESY spectra
g
revealed characteristic NOEs between C H (i) and NH (i +
g
Table 2: Comparison of the backbone torsion angles of the Z-vinylogous
g-amino acids with other g-residues in a,g-hybrid 12-helices.
2), as well as between C H (i) and NH (i + 1). All unambig-
uous NOEs observed in the P1 and P5 are tabulated in the
Supporting Information. The NOE pattern we observed is
consistent with the NOEs observed for reported 12-helix
a,g-hybrid 12-Helix
f
q1
51Æ28
q2
y
4
[12g]
g -AA
À124Æ68
À124Æ48
62Æ38 À122Æ98
64Æ88 À112Æ108
[11e,22]
3
,3
[10]
solution structures.
Based on the experimentally
g
-AA
56Æ68
2
,3,4
[11a]
deduced NOEs, calculation of solution structures were
g
-AA (cyclic)
140Æ108 À56Æ28 À52Æ28
111Æ48
[
8b]
Theoretical model
À122Æ28
À129Æ98
À120Æ28
À119Æ48
52Æ28
56Æ28
50Æ58
100Æ58
62Æ28 À125Æ48
55Æ28 À120Æ98
64Æ28 À127Æ28
performed by using distance restrained molecular dynamic
2
,3
[11e]
[23]
g
g
-AA (cyclic)
simulations as reported earlier.
The overlay of 10 low-
3
,4
[12i]
- AA
energy conformers of NMR-calculated structures of P1 and
P5 are shown in Figure 3A. The solution structures showed
excellent correlation with the conformation in single crystals.
4
Z-g
0Æ38
À78Æ48
(Present work)
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A superimposition of the solution and crystal conformations
of P5 is shown in Figure 3B.
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In conclusion, we present single-crystal and solution
conformations of novel a,g-hybrid peptide 12-helices com-
posed of Z-vinylogous amino acids. The results suggest that Z-
vinylogous residues show an intrinsic tendency to adopt
helical conformation, however, with a distinct new set of
backbone torsion angles compared to the other g-amino acids.
Remarkably, the cis double bonds and carbonyl groups in Z-
vinylogous residues showed no p conjugation compared to
their (E)-isomers in hybrid peptides. The deviation from
planarity of the carbonyl-conjugated double bonds in the
helix may be dictated by the strength of canonical intra-
molecular H-bonds. These novel non-classical helices with
functionalizable carbon–carbon double bonds in the back-
bone may provide new opportunities in the design of func-
tional peptide foldamers. We are currently exploring the
chemical reactivity of these unsaturated helices.
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