A Pure Polyproline Type I-like Peptoid Helix by Metal Coordination

Article abstract of DOI:10.1002/chem.201704497

Peptoids, N-substituted glycine oligomers, are an important class of foldamers that can adopt polyproline-type helices (PP-I and PP-II), given that the majority of their sequence consists of chiral, bulky side chains. Herein a new approach for the stabilization of a pure PP-I-like peptoid helix through metal coordination is introduced. A systematic spectroscopic study was performed on a series of peptoid heptamers bearing two 8-hydroxyquinoline ligands at fixed positions, and a mixture of chiral benzyl and alkyl substituents in varied positions along the peptoid backbone. When the benzyl groups are located at the 3rd and 4th positions, the peptoid (7P6) gives upon Cu²⁺ binding a circular dichroism (CD) signal similar to that of a PP-I helix. Exciton couplet CD spectroscopy and EPR spectroscopy, as well as modifications to the length of 7P6 and derivatization through acetylation provided insights into the unique folding of 7P6 upon Cu binding, showing that it is led by two competing driving forces, namely coordination geometry and sequence.

Full text of DOI:10.1002/chem.201704497

A Journal of
Accepted Article
Title: A Pure Polyproline Type I-like Peptoid Helix via Metal
Coordination
Authors: Galia Maayan, Lieby Zborovsky, Alisa Smolyakova, and Maria
Baskin
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To be cited as: Chem. Eur. J. 10.1002/chem.201704497
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A Pure Polyproline Type I-like Peptoid Helix via Metal
Coordination
Lieby Zborovsky[a], Alisa Smolyakova[a], Maria Baskin[a] and Galia Maayan*[a]
Abstract: Peptoids, N-substituted glycine oligomers, are an
important class of foldamers that can adopt polyproline type helices
(PP-I and PP-II), given that the majority of their sequence consists of
chiral bulky side chains. Herein we introduce a new approach for the
stabilization of a pure PP-I-like peptoid helix via metal coordination.
We performed a systematic spectroscopic study on a series of
peptoid heptamers baring two 8-hydroxyquinoline ligands at fixed
positions, and a mixture of chiral benzyl and alkyl substituents in
varied positions along the peptoid backbone. We found that when
the benzyl groups are located at the 3rd and 4th positions, the peptoid
(7P6) gives upon Cu2+ binding a CD signal similar to that of a PP-I
helix. Exciton couplet CD and EPR spectroscopies, as well as
modifications to the length of 7P6 and acetylation provided insights
into the unique folding of 7P6 via Cu binding, showing that it is led by
local steric and stereo-electronic interactions.8 In contrast to
polyproline peptides that are composed of either cis or trans
amide bonds, peptoid monomers can favor both cis and trans
orientation of the amide bond. This can be easily evidenced from
circular dichroism (CD) spectroscopy, which is a key tool for
describing the secondary structure of peptoids. Typical CD
spectra of peptoids having only alpha-methyl-benzyl side chains
(alpha-methyl-benzyl peptoids), for example, measured in
organic solvents such as methanol and acetonitrile, exhibit
double minima near 200 and 220 nm due to the presence of
both the trans- and cis-amide bonds, respectively.9 This is
because alpha-methyl-benzyl peptoids, although generally
adopting PP-I type helices with a pitch of three residues per
turn,9,10 contain a minor population of conformers consisting of
two competing driving forces – coordination geometry and sequence. one or more trans-amide bonds.9 As a consequence, controlling
peptoids conformation is not trivial, and thus, a major objective is
to produce all-cis PP-I-like peptoid helices as a basis for further
applications in biology,3 asymmetric catalysis,11 selective
recognition5i,j,m and more.12 Efforts towards this goal focus on the
development of chiral bulky side chains that could grant a
considerable energetic preference for the cis amide bond
conformation.13 These efforts resulted in the four best cis-
directing side chains reported to date, namely triazole-based
side chains,14 (S)-N-(1-naphthylethyl)glycine (Ns1npe),15 tert-
butyl (t-Bu) and (S)-N-(1-tert-butylethyl)glycine (Ns1tbe). 16 Each
side chain was used for the construction of peptoid homo-
oligomers with various lengths exhibiting all-cis PP-I-type helices,
as demonstrated by high-resolution structural studies including
X-ray crystallography and NMR spectroscopy, as well as from
CD spectroscopy. Notably, the CD spectra of oligomers with six
to nine Ns1tbe monomers represent an exceptional example in
which their CD spectra resembles this of a PP-I-type peptide
helix. Although these structures are quite remarkable, they are
also unique, limiting drastically the sequence and functional
diversity of all-cis PP-I-type peptoid helices, which presently, can
only be generated from four specific side chains out of the
numerous ones that exist. Therefore, an entirely different
approach towards the formation of pure PP-I peptoid helices
should be considered in order to increase peptoid helices
diversity, and may be developed by the use of metal
coordination, which proved efficient in the case of peptide
helices stabilization.17 Moreover, understanding the relationship
between peptoids folding and metal binding should shed some
light on the relationship between peptoid structure and function
in general, enhancing the knowledge in this field, which is still
lacking thus limiting the applications of metallopeptoids.
Introduction
Folding of natural biopolymers is an important event, in which
specific arrangements of various functional groups lead to the
creation of reactive centers. The established relationship
between the structure and function of natural biopolymers has
inspired the design of ‘‘foldamers’’1 — biomimetic oligomers that
fold into three-dimensional structures in solution. Peptoids,
oligomers of N-substituted glycine, are an important class of
peptide mimics capable of forming well-defined secondary
structures,2 and performing various biological functions.3 Peptoid
oligomers can be synthesized efficiently by solid-phase
methods,4 granting the facile utilization of a large scope of side
chains, thus allowing the introduction of different functional
groups.2 One example is the incorporation of metal binding
ligands aiming to form metallopeptoids.5-7 This has led to peptoid
chelators, which were utilized for the synthesis of metal
containing biomimetic scaffolds with intriguing properties, and
some were applied in selective recognition and catalysis.5-7
Although peptoids are incapable of forming hydrogen-
bonded networks along the backbone, many peptoid sequences
exhibit a remarkable tendency for folding.2 It was previously
demonstrated that peptoids, which at least two thirds of their
backbones consist of bulky N-α-chiral residues, are capable of
adopting polyproline-like helical secondary structures due to
[a] Dr. Lieby Zborovsky, Alisa Smolyakova, Maria Baskin, Prof. Galia
Maayan.
Earlier work by Maayan et al. demonstrated that the
incorporation of two 8-hydroxyquinoline (HQ) groups within the
backbone of a helical peptoid, with chiral-bulky (S)-(-)-1-alpha-
methyl-phenylethylamine (Nspe) substituents (H26, Fig. 1a, top)
can be utilized for intramolecular binding of copper and cobalt
metal ions.6 Interestingly, metal binding to the HQ groups, which
Schulich Faculty of Chemistry,
Technion- Israel Institute of Technology
Haifa, 32000, Israel.
Email: gm92@technion.ac.il
Supporting information for this article is given via a link at the end of the
document.
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were located at 2nd and 5th positions (i and i+3), affected the
peptoid secondary structure and increased the peptoid helicity
as was evidenced by the enhanced intensity of the CD double
minima signal at about 200 and 220 nm (Fig. 1a, bottom).6
Inspired by this report, we recently attempted to induce
secondary structure by metal binding to a completely unfolded
peptoid.7 We expected that metal binding would tighten the
peptoid backbone resulting in a more helical structure. Thus, a
water-soluble heptameric peptoid (7mer-HQ2, Fig. 1b, top),
having two HQ groups located at the 2nd and 5th positions, and
five chiral non-bulky N-S-methoxy-propyl (Nsmp) groups was
synthesized.7 Nsmp groups are not bulky enough to induce
secondary structure. However, the chirality of the Nsmp groups
allows the analysis of the secondary structure by CD.
Disappointingly, no helix formation was observed upon binding
of copper or cobalt ions, as was learned by analyzing the CD
spectra of the free 7mer-HQ2 (Fig. 1b, bottom, blue line) and its
copper and cobalt complexes (Fig. 1b, bottom, red and green
lines, respectively) in the range of 190-230 nm, all of which
suggest completely disordered structures.7 These results imply
that a helical structure cannot be induced solely by metal
coordination. Overall these studies demonstrate that metal
binding can increase the helicity of Nspe peptoids while
maintaining the mixed population of PP-I- and PP-II-like helices,
on one hand, and cannot affect the helicity of disordered
peptoids on the other hand. Accordingly, we wished to attempt
the formation a pure PP-I-like peptoid helix upon metal binding,
which will give rise to a CD spectrum that resembles this of a
PP-I peptide helix. To this aim, we decided to investigate
coordination of metal ions to peptoids that exhibit low intensity
double minima in the CD spectra, and try to increase the cis-
amide bonds population while decreasing the trans-amide bond
population.
these positions was expected to provide a more efficient metal
binding and a tighter structure.6 It is known from previous
literature that the driving force for folding of peptoids is the
incorporation of at least 66% chiral-bulky side chains out of all
the substituents within the sequence.2 Our strategy was to
reduce the peptoid helicity by using less than 66% of chiral-bulky
substituents and to attempt the increasing of its helicity by metal
coordination. Thus, peptoid 7P1 was synthesized with one Nspe
group at the 1st position (14% of the monomers) and 7P2 was
synthesized with two Nspe groups in the 1st and 7th positions
(28% of the monomers). A key parameter that determines the
helicity of the peptoid backbone is the position of the Nspe
groups along the peptoid chain.20 Thus, oligomers 7P3-7P7
were designed to have alterations in the sequence of 7P2 such
that the two Nspe groups are shifted to different positions along
the peptoid chain. As an example of a fully helical peptoid that
can serve as a reference point, 7P8 with five Nspe groups was
synthesized. All peptoids were synthesized on solid support
followed by their cleavage at the end of the synthesis and
purification by HPLC (>95%). The molecular weights measured
by electrospray mass spectrometry (ESI-MS) were consistent
with the expected masses (see SI).
In this article we report the design, synthesis and
characterization of a series of peptoid oligomers containing a
combination of chiral-bulky and chiral-non-bulky substituents.
We study the effect of metal binding on the formation of peptoid
helical structures and demonstrate the ability to increase the
population of the cis-amide bond conformers by metal binding,
as evident from CD spectroscopy. We show that the largest
effect of metal binding is in the case of a “bulky-core” peptoid
having two Nspe groups at the 3rd and 4th positions that give rise
to a low intensity double minima CD spectrum; upon Cu2+
coordination, the CD spectrum drastically changes and
resembles a typical CD spectrum of a PP-I helical peptide and
the CD spectra of the all-cis Ns1npe and Ns1tbe based PP-I
peptoid helices.
Results and Discussion
Design and synthesis of peptoid oligomers: Eight peptoid
oligomers, 7P1-7P8 (Fig. 1c) were synthesized, using 8-
hydroxy-2-quinolinemethylamine (HQ), (S)-(-)-1-alpha-methyl-
phenylethylamine (Nspe) and (S)-(+)-1-methoxy-2-propylamine
(Nsmp) as synthons, employing ‘‘submonomer’’ protocols.18 HQ
is a strong chelator for divalent metal ions such as Co2+, Cu2+
and Zn2+.19 All peptoids consist of seven monomers and bare
two HQ groups incorporated at the 2nd and 5th positions. These
positions were chosen in accordance with the 3 residues per
turn structure of the peptoid helix.6 Placing the HQ groups in
Figure 1. (a) Chemical sequence of H26 and CD spectra of H26 and its Cu2+
complex.6 (b) Chemical sequence of 7mer-HQ2 and CD spectra 7mer-HQ2
and its metal complexes7.(c) Chemical sequences of oligomers 7P1-7P8.
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UV-Vis analysis: The metal-free peptoids exhibited absorption
bands near λ=245 nm and 306 nm in 80% aqueous methanol
solution. Upon addition of metal acetate (M(Ac)2 M= Co, Cu, Zn),
binding of M2+ produced new absorption bands at λ = 265, 383
7P2 from the 1st to the 4th position, to give 7P7, results in an
expected decrease of the CD intensity and a nearly complete
loss of the double minima (Fig. 3g). Oligomer 7P6 with the two
Nspe groups located at the 3rd and 4th positions, between the
two HQ groups, showed pronounced double minima at 200 nm
and 220 nm (Fig. 3f). The intensity of the double minima,
especially the peak at 220 nm, which corresponds to the cis
nm for Zn2+ and Co2+ and
λ =
265, 390 nm for Cu2+.
Representative plots are depicted in Fig. 2, showing the
absorbance band of the free peptoids in red and the absorbance
band of their Cu2+ complexes in blue (for other plots see SI).
Titration experiments with M(Ac)2 using UV-Vis spectroscopy
confirmed that the complexes are formed in 1:1 metal to peptoid
ratio (Fig. 2, insets). This ratio suggests that the metal is bound
in an intramolecular mode to two HQ ligands, and this was
further supported by ESI-MS (see SI).
amide bond, indicates
a more ordered helical structure
compared with 7P1-7P5. This result is surprising because 7P6
does not possess a bulky-chiral group at the crucial 1st position.
This observation can probably be attributed to the formation of a
“bulky-core” segment in the middle of the peptoid sequence that
promotes the formation of a helical secondary structure. 7P8
(Fig. 3h) substituted by five Nspe groups, which was
synthesized as a control peptoid for comparison with the other
Nspe peptoids, exhibited, as expected, the most ordered
structure as can be seen from the relatively high intensity CD
signal with distinct double minima at 200 nm and 220 nm. In
addition to the CD signals in the range of 190-230 nm, all metal
free peptoids exhibit a CD peak at about 250 nm. This peak
corresponds to the absorption of the HQ ligand as was shown by
UV measurements (Fig. 2). As the HQ ligand is achiral, its
appearance in the CD spectra indicates chiral induction from the
peptoid backbone.
Figure 2. UV titrations of (a) 16.6 µM 7P6 and (b) 16.6 µM 7P8 with Cu(Ac)2 in
80% aqueous MeOH.
CD analysis: The CD spectra of all peptoids were measured in
80% aqueous methanol. Peptoid 7mer-HQ2, with no bulky-chiral
groups, shows no double minima in the CD spectrum indicating
its disordered secondary structure (Fig. 1a).7 Aiming to explore
whether we can initiate helicity within this peptoid, we replaced
the Nsmp group in the first position by an Nspe group, because
this position of the peptoid sequence was shown to determine
the peptoid helicity according to the “sergeant-soldiers” effect.20
Indeed, the CD spectra of 7P1 with only one Nspe group at the
1st position demonstrates low intensity double minima consistent
with the initiation of a helical structure formation (Fig. 3a).
Binding of either Co2+ or Zn2+ did not have a significant effect on
the CD spectrum of the unbound peptoid, while the binding of
Cu2+ results in a decrease in the intensity of the spectrum. The
latter can be attributed to structural changes within the peptoid,
enforced by the coordination geometry of the copper complex. In
attempts to further explore this, we replaced one more Nsmp
group by an Nspe group. Thus, we synthesized oligomers 7P2-
7P5, which have an Nspe group in the 1st position but differ in
the position of the other Nspe group that is located at the 7th, 6th,
4th and 3rd position respectively. From examining the CD spectra
of these oligomers, we can see that all of them have some
extent of helicity that can be attributed to the Nspe group at the
determining 1st position.20 However, the intensity of the double
minima depends strongly on the position of the second Nspe
group. Thus, oligomers 7P2 (Fig. 3b) and 7P3 (Fig. 3c), with the
second Nspe group at the 7th and 6th positions respectively,
exhibit low intensity, mostly disordered CD spectra, while
oligomers 7P4 (second Nspe group at the 4th position, Fig. 3d)
and 7P5 (second Nspe group at the 3rd position, Fig. 3e) show a
higher intensity signal compared with that of 7P2 and 7P3, with
a more pronounced double minima around 200 nm and 220 nm
indicating a more helical structure. Shifting the Nspe group of
Figure 3. CD spectra of oligomers 7P1-7P8 and their Co2+, Cu2+, Zn2+
complexes (100 µM in 80% aqueous methanol).
In all cases except for 7P6, addition of Zn2+ or Co2+ has only
a small effect on the CD spectrum of the peptoids in the near-UV
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region. Binding of Cu2+ results in the decrease of CD intensity for
7P5, 7P7 and 7P8 and does not change the CD spectrum of
7P2, 7P3 and 7P4. As discussed above, the CD spectra of the
free peptoids 7P5, 7P7 and 7P8 exhibit some degree of helicity
as indicated by the typical double minima signal, while 7P2, 7P3
and 7P4 do not. Notably, the coordination geometry of the
formed copper complexes enforces structural changes (as was
observed in the case of 7P1) only within the peptoids that have
some secondary structure prior to Cu2+ binding. Specifically, in
7P4, which exhibits low-intensity double minima, an increase in
the intensity of the band at 200 nm is observed compared to the
band at 220 nm that does not change at all. This observation
suggests an increase in the population of the trans-amide bond
conformers of this peptoid in solution upon Cu2+ binding, and an
overall decrease in the stability of its PP-I helical structure. On
the other hand, in 7P8, with the most intense double minima, a
more pronounced decrease in the intensity of the band at 200
nm is observed compared to the band at 220 nm, suggesting a
decrease in the population of the trans-amide bond conformers
of this peptoid in solution and an overall increase in the stability
of its PP-I helical structure. The latter observation is further
demonstrated by oligomer 7P6, which shows the largest effect of
metal binding. Coordination of Co2+ results in a significant
decrease in the CD intensity of both minima, suggesting the
destruction of the secondary structure, probably due to geometry
coordination considerations (Fig. 3f, red line). The binding of
Zn2+ resulted in a significant decrease only in the band at about
200 nm, which corresponds to the trans amide bond, suggesting
a change in the structure of the peptoid, not its destruction (Fig.
4F, blue line). Surprisingly, coordination of Cu2+, results in a CD
signal completely different from that of the free peptoid,
exhibiting minima at 200 and 226 nm and a maximum at 212 nm
(Fig. 3f green line, Fig. 4a). These spectra closely resemble this
of a PP-I peptide helix21 (Fig. 4b), as can be observed from the
comparison of the two spectra in Fig. 4, and the CD spectra of
the all-cis Ns1npe and Ns1tbe based PP-I peptoid helices.
Based on the experimental CD spectrum of 7P6Cu, we propose
that coordination of copper ions to 7P6 results in the formation of
a pure PP-I-like helical structure. We assume that the driving
force for the formation of this exceptionally ordered helix is the
initial secondary structure of 7P6 as implied from the low
intensity double minima observed in its CD spectra combined
with the coordination geometry of its Cu complex. All-cis PP-I-
like peptoid helices were previously observed for bulky aliphatic
peptoids16, 22 or for chiral bulky substituted peptoids.15 Herein, we
demonstrate the possibility of achieving a pure PP-I helical
structure for mixed aliphatic-aromatic substituted oligomers.
Binding of Zn2+, Co2+ or Cu2+ ions to oligomers 7P1-7P8,
results in the appearance of exciton couplet peaks in the far UV
region, located between 240 and 280 nm, and represented by
two coupled absorption bands with opposite signs, known to be
caused by the interaction between two chromophores present in
the same backbone.23 It was previously demonstrated both by
computational and empirical methods that the intensity and
wavelength of the exciton couplets depend on the dihedral angle
between the two chromophores.23 As the angle between the
chromophores increases, the CD magnitude decreases and
slightly shifts toward the UV region.23 In this work, the two
chromophores correspond to the two HQ side chains; hence, the
angle between these ligands is correlated to the coordination
geometry of the metal complex formed. As can be seen in the
CD spectra, there is a difference in the intensity of the exciton
couplet for complexes of the same peptoid with different metal
ions (Fig. 3). We assign these differences to the dissimilarity in
coordination geometry of the HQ ligands with each metal ion.
Moreover, when comparing the exciton couplet peaks of
different oligomers with the same metal ion, e.g. Cu2+,
differences in intensities are observed (Fig. 5a). Thus, peptoids
with more ordered secondary structures e.g. 7P5, 7P6 and 7P8,
exhibit the lowest intensities of the exciton couplet peak,
indicating larger dihedral angles between the HQ chromophores.
This increase in the dihedral angles, which ultimately leads to a
distortion from the preferred coordination geometry of the metal
center, can be attributed to the larger steric hindrance that is
obtained for the more ordered peptoid structures.7 (HQ)2Cu, for
example, is known to adopt the square planar geometry,24 but
when this complex is incorporated within a helical peptoid, the
peptoid scaffold enforces an unusual coordination environment,
leading to the formation of a pseudo-tetrahedral metal complex.6
Figure 5. (a) Far UV CD spectra of peptoid copper complexes 7P1Cu-7P8Cu
(100 µM in 80% aqueous methanol). (b) Room temperature X-band EPR
spectra of peptoid oligomer copper complex 7P6Cu in solid state (blue line)
and the corresponding simulated spectra (red line). Reference - TEMPO
(marked by *), g = 2.0058.
EPR analysis: In order to get some more information about the
structure of the copper complexes and establish our hypothesis
regarding the relationship between the peptoids helicity and
coordination geometry of their metal centers, we conducted EPR
measurements to all the Cu-peptoids. Cu2+ complexes have a
3d9 electronic configuration making them paramagnetic with an
electronic spin of 1/2, allowing the measurement of their electron
paramagnetic resonance (EPR) spectra. EPR measurements
can not only confirm the presence of Cu2+ in the compound but
also give insight into the geometry of the formed complex. It was
previously suggested that the quotient (g||)/(A||) [cm] is a reliable
parameter for determining coordination geometry of tetra-
Figure 4. (a) CD spectrum at near-UV of 7P6Cu (100µM in 80% aqueous
methanol). (b) near-UV CD spectrum of PP-I peptide helix.21
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coordinated Cu(II) complexes; it ranges between 105 to 135 for
square-planar structures and indicates tetrahedral distortion
when higher than 135.25 For (HQ)2Cu the experimental value of
the quotient is 134, consistent with its square-planar geometry.26
For 7mer-HQ2 the experimental quotient value was 137,
indicating a slight distortion of planarity assigned to the effect of
the peptoid backbone on the geometry of the complex.6 In
analogy with (HQ)2Cu and 7mer-HQ2, oligomers 7P1-7P8 are
anticipated to form tetragonal complexes when bound to Cu2+.
The quotient value for these complexes is expected to be higher
than 135, as a result of a distortion from square-planar geometry
caused by the peptoid backbone. Thus, the X-band EPR spectra
of solid, powdered samples of (L)Cu(PF6) (L = 7P1-7P8) were
recorded at room temperature (a representative spectrum of
7P6Cu appears in Figure 5b). The EPR signals clearly indicated
the presence of a Cu2+ and the Hamiltonian parameters obtained
from their spectra are summarized in Table 1. The experimental
values of the quotient (g||)/(A||) [cm] derived from our EPR
measurements are about 135-136 for the complexes 7P1Cu-
7P5Cu and 7P7Cu, indicating a very slight distortion from
square-planar geometry. The quotient of 7P6Cu is 138, implying
that it is more distorted towards a tetrahedral geometry. For the
helical peptoid complex 7P8Cu the quotient value is 155. This
value corresponds to a tetrahedral geometry of the complex.
These results are in line with the assumption that the structure of
the peptoid backbone affects the geometry of the formed
complex. Thus, a more helical peptoid results in an increased
steric bulk around the metal center causing the distortion of the
square planar structure. These results are in a good correlation
with the CD measurements (Fig. 3) that show that the copper
complexes 7P6 and 7P8 possess a more ordered helical
structure that complexes 7P1-7P5 and 7P7.
formation of the copper complex 7P6Cu has an overall
stabilizing effect on the peptoid secondary structure, which leads
to a higher thermal stability of 7P6Cu in comparison with the
free 7P6. The positive peak of the exciton couplet, near 275 nm
also increases with raising the temperature. As the increase in
exciton couplet correlates with the decrease in dihedral angle
between the two HQ chromophores,23 we can assume that the
increasing of temperature results in a change in the coordination
geometry about the metal center.
Understanding the factors that contribute to the unique
structure of 7P6Cu: Aiming to understand the role of the “bulky-
core” motif in the formation of the PP-I secondary structure in
7P6, we synthesized the “bulky-core” fragment (peptoid tetramer
4P6, Fig. 6) with HQ groups at the 1st and 4th positions and Nspe
groups at the 2nd and 3rd positions. The CD spectra of 4P6
before and after Cu2+ addition were recorded. While the free 4P6
gives a CD spectrum similar to double minima typical for Nspe
peptoids (see SI), addition of copper leads to a decrease in the
CD intensity and the band about 220 nm becomes predominant
(Figure 7a, black line). This spectrum, however, do not resemble
that of a PP-I helix. Thus, the “bulky-core” by itself is not the only
requirement for the formation of a pure PP-I-like peptoid helix
upon copper binding, probably because the overall peptoid
sequence is too short.15 Consequently, we synthesized three
more peptoids, namely 6P6, 7P6I and 8P6 (Fig. 6), all containing
the “bulky-core” motif, and measured their CD spectra before
and after Cu2+ addition. Oligomer 6P6 is a symmetrical hexamer
with an Nsmp group at the first and last positions. 7P6I is a
modified 7P6 with two Nsmp groups near the N-terminus and
one Nsmp group near the C-terminus. Aiming to probe the effect
of the longer Nsmp tail near the C-terminus, we extended 7P6I
by one Nsmp monomer to give 8P6, a symmetrical octamer with
two Nsmp groups before and after the “bulky-core” fragment.
Table 1. Hamiltonian parameters of copper complexes LCu (L=7P1-7P8).a
Complex
ꢀ∥
ꢀ!
ꢀ∥×ꢀꢁ!ꢀ, ꢀꢁ!ꢀ
ꢀꢀ∥, ꢀꢁ
∥
(HQ)2Cu26
2.172
2.230
2.042
2.071
162.0
164.5
134
136
7P1Cu
7P2Cu
7P3Cu
7P4Cu
7P5Cu
7P6Cu
7P7Cu
7P8Cu
2.220
2.235
2.230
2.220
2.250
2.206
2.560
2.067
2.067
2.063
2.063
2.065
2.065
2.066
162.7
165.9
164.5
164.8
162.8
163.3
164.7
136
135
136
135
138
135
155
Figure 6. Chemical sequences of oligomers 4P6, 6P6, 7P6I and 8P6.
[a] All measurements were performed in the solid state at rt., with TEMPO as a
reference (g = 2.0058).
The CD spectra of these three peptoids exhibited the typical
double minima of Nspe peptoids, only with an intensity of about
a third compared to this of 7P8 (Fig. S80b-d, black lines).
Addition of Cu2+ to each of these three peptoids results in a
decrease in the intensity of the band at about 200 nm and an
increase in the intensity of the band at about 220 nm, which is
also red-shifted. In the case of 6P6 and 7P6I this effect is similar
to the one observed for the “bulky-core” segment 4P6, but
although it is more pronounced, these spectra still do not
resemble that of a PP-I helix (Fig. 7a). Oligomers 7P6 and 7P6I
have the same monomer composition but differ in the number of
the Nsmp side-chains near the N-terminus. 7P6 has the two
Variable temperature CD measurements: To test the thermal
stability of the obtained pure PP-I-like structure, we performed
CD measurements both to 7P6 and 7P6Cu complex at
temperatures ranging from 5°C to 60°C (see SI). The CD
intensity of free peptoid 7P6 is decreased with temperature
increase, indicating that the overall population of the ordered
peptoid in solution is decreased. However, for the copper
complex 7P6Cu only a very slight decrease of the CD intensity
at temperatures above 30°C is observed. This implies that
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Nsmp monomers near the N-terminus and 7P6I has only one
Nsmp monomer near the N-terminus. However, this small
difference is crucial for the PP-I helix formation. In the case of
8P6, Cu2+ binding leads to a CD spectrum with two minima at
196 nm and 222 nm and a maximum at 206 nm (Fig. 7a, pink
line). This signal closely resembles that of a PP-I helix and is
very similar to the spectrum recorded for 7P6 (Fig. 7a, blue line).
From these results it can be concluded that the combination of a
“bulky-core” motif and at least two Nsmp monomers near the N-
terminus, is required for the formation of the PP-I helix upon
Cu2+ coordination. This effect can be assigned to the previously
described concept of cooperative folding. Thus, longer peptoid
oligomers show more folded secondary structures.22
terminus influenced dramatically the geometry of the Cu2+
complex. As the higher intensity of the exciton couplet correlates
with the smaller dihedral angle of the complex,23 we can assume
that the terminal N-H has a significant contribution to the
geometry of the copper complex. This contribution was lost upon
acetylation leading also to the changes in the PP-I helix. The
effect of the acetylation can be assigned to the loss of the
hydrogen bonding from the N-H group to the peptoid backbone
that decreases the helicity of the peptoid.15a This results in a less
ordered secondary structure and hence less steric hindrance
about the copper center. An alternative explanation would be the
intramolecular coordination of the N-H group to the metal center
resulting in a tighter helical structure and a more hindered
geometry about the copper ion. This coordination would be
geometrically possible only for 7P6 and 8P6, having two Nsmp
side-chains near the N-terminus (in terms of N-H accessibility to
the metal ion), and thus, the effect of N-terminus acetylation is
not observed for 6P6 having only one Nsmp side chain.
However, our UV –Vis titrations and EPR data, which collectively
suggest that both HQ ligands are bound to the metal ion in
tetragonal coordination geometry, do not support this
explanation.
Conclusions
This work describes the use of metal coordination as a new
platform for peptoid folding. Although both the structure and
function of peptoids have been extensively explored, and
despite the well-established relationships between sequence
structure and function in biopolymers, knowledge about these
relationships in peptoids is still lacking, limiting their current
applications in all fields. In this paper we present a systematic
study on the secondary structure of peptoid oligomers with
mixed chiral aromatic and aliphatic side chains, before and after
metal ions addition. We demonstrate that Cu2+ coordination to a
“bulky-core” peptoid oligomer, bearing two chiral alpha-methyl-
benzyl groups at the 3rd and 4th positions and two HQ ligands at
the 2nd and 5th positions, results in the formation of a stable
polyproline type I-like helical secondary structure as evidenced
by CD measurements and further supported by EPR
spectroscopy. This is in fact the first example of generating a
stable helical secondary structure of a peptoid by means of
metal coordination. We show that peptoids, in which chiral bulky
side chains do not constitute the majority of their sequences,
can fold into pure PP-I-like helices upon metal binding, thus,
expending the diversity of structured peptoid that can be
constructed. Based on systematic studies by CD and EPR
spectroscopies, we describe, for the first time, the relationship
between the peptoids structure and the coordination geometry of
their metal center. We observe the following clear trend within
Cu-peptoid complexes: the larger the angle between the two HQ
groups is (detected by the lower exciton coupled CD intensity),
the larger is the distortion of the metal center from square planar
geometry towards tetrahedral geometry (found from the EPR
data) and the more ordered is the peptoid secondary structure
(as seen by near-UV signals in the CD spectra). We discovered
that in contrast to other peptoid helices, which can be further
stabilized by N-terminus acetylation, metallopeptoid helices are
destabilized by this acetylation, hence, the terminal N-H group
has a significant role in peptoid folding upon metal coordination.
Figure 7. CD spectra of (100 µM in 80% aqueous methanol): (a) Cu2+
complexes of 4P6, 6P6, 7P6, 7P6I, 8P6. (b) Cu2+ complexes of 6P6 and
6P6Ac (c) Cu2+ complexes of 7P6 and 7P6Ac (d) Cu2+ complexes of 8P6 and
8P6Ac.
It was previously demonstrated that acetylation at the N-
terminus of PP-I peptoids can further stabilize their helical
structures.15,16 To test this observation in our case, we
synthesized oligomers 6P6Ac, 7P6Ac and 8P6Ac that have the
same monomer sequence as 6P6, 7P6 and 8P6 respectively but
are acetylated. Their CD spectra before and after Cu2+ addition
were recorded and compared with their non-acetylated
prototypes. For 6P6Ac and 7P6Ac the CD spectra of the free
peptoids are very similar in shape and intensity to the spectra of
the free 6P6 and 7P6 respectively (Fig. S81). For 8P6Ac the CD
spectrum is of similar shape and a somewhat lower intensity
compared with 8P6 (Fig. S81). These results indicate that the
acetylation of the N-terminus has little or no effect on the
secondary structure of the free peptoids. The CD spectrum of
the Cu2+ complex of the acetylated 6P6Ac is also very similar to
the spectrum obtained for the Cu2+ complex of its non-acetylated
analogue 6P6 (Fig. 7b). In contrast, the CD spectra of the Cu2+
complexes of the acetylated peptoids 7P6Ac and 8P6Ac were
found to be very different from that of their non-acetylated
prototypes (Fig. 7c, 7d). In both cases, the characteristic peaks
of the PP-I helix are lost and the CD spectra show typical double
minima near 195 nm and 220 nm, with the larger peak at about
220 nm. In addition, there is a five-fold increase in the intensity
of the exciton couplet at the far UV area between 260 nm and
280 nm. This increase indicates that the acetylation of the N-
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of a 1.2 M solution of bromoacetic acid, 0.04 ml of neat N, N’-
diisopropylcarbodiimide (DIC) and 0.29 ml of DMF were added to the
resin and mixed at room temperature for 20 minutes.18
Our findings reveal that the effect of metal binding on the
peptoid’s structure depends both on the peptoid’s sequence
(leading to its initial secondary structure), and on the preferred
coordination geometry of the metal ion. These two competing
driving forces for peptoid folding can be controlled by sequence
design and choice of (i) the number and position of bulky chiral
groups, (ii) the type of binding ligands and (iii) the type of metal
ions. We believe that our findings introduce a new platform in
peptoid folding, as well as in peptidomimetics structural
stabilization, which can impact the design of novel functional
biomimetic compounds with diverse sequences.
Acetylation of the peptoid oligomers. After completion of the peptoid
synthesis, 0.17 ml of a 1.2 M solution of acetic acid, 0.04 ml of neat N,
N’-diisopropylcarbodiimide (DIC) and 0.29 ml of DMF were added to the
resin and mixed at room temperature for 60 minutes.
Cleavage and Purification of the Peptoid Oligomers. When the
desired sequence was achieved, the peptoid products were cleaved from
the resin by treatment with 95% trifluoroacetic acid (TFA) in water (50 mL
g-1 resin) for 30 minutes. After filtration, the cleavage mixture was
concentrated by rotary evaporation under reduced pressure for large
volumes or under a stream of nitrogen gas for volumes less than 1 mL.
Cleaved samples were then re-suspended in 50% acetonitrile in water
and lyophilized to powders. Peptoids were purified by preparative High
Experimental Section
Materials. Rink Amide resin was purchased from Novabiochem;
Trifluoroacetic acid (TFA), Zinc acetate dehydrate and Nickel acetate
tetrahydrate, (S)-(+)-1-methoxy-2-propylamine (Nsmp) were purchased
from Alfa Aesar; 8-hydroxy-2-quinolinecarbonitrile, (S)-(-)-1-Alpha-
Performance Liquid Chromatography (HPLC) using
a C18 column.
Products were detected by UV absorbance at 230 nm during a linear
gradient conducted from 5% to 95% solvent B (0.1% TFA in HPLC grade
acetonitrile) over solvent A (0.1% TFA in HPLC grade water) in 50
minutes with a flow rate of 5 mL min-1.
methyl-phenylethylamine (Nspe), 4'-Chloro-2,2':6',2''-Terpyridine
and
Manganese acetate tetrahydrate were purchased from Acros;
Bromoacetic acid, cobalt acetate tetrahydrate and copper acetate
monohydrate were purchased from MERCK; N,N’diisopropylcarbodiimide
(DIC), piperidine, benzylamine, acetonitrile (ACN) and water HPLC grade
solvents were purchased from Sigma-Aldrich; dimethylforamide (DMF)
and dichloromethane (DCM) solvents were purchased from Bio-Lab Itd.
These reagents and solvents were used without additional purification.
Synthesis of metal complexes for MS analysis. Samples for MS
analysis were prepared shortly before measurements. Typically,
a
solution of peptoid oligomers (100-200 µL 0.5mM) in MeOH or ACN was
treated with metal solution (5mM in H2O or ACN) and the mixture was
stirred for 30 minutes and sent to MS analysis.
UV-Vis analysis. Metal binding of peptoid oligomers with metal ions Cu2+
Co2+ and Zn2+ was analyzed by titration experiments using UV-VIS
measurements. In a typical experiment, 10 µL of a peptoid solution (5
mM in methanol) was diluted in 3 ml of 80% aqueous methanol (16.6 µM
final concentration) and then sequentially titrated with 2 µL aliquots of a
metal ion (5 mM in H2O), in multiple steps, until the binding was
completed.
,
Instrumentation. Peptoid oligomers were analyzed by reversed-phase
HPLC (analytical C18(2) column, Phenomenex, Luna 5µm, 100 Å, 2.0x50
mm) on a Jasco UV-2075 PLUS detector. A linear gradient of 5–95%
ACN in water (0.1% TFA) over 10 min was used at a flow rate of 700
µL/min. The spectrum was recorded at 214 nm. Preparative HPLC was
performed using a AXIA Packed C18(2) column (Phenomenex, Luna
15µm, 100 Å, 21.20x100mm). Peaks were eluted with a linear gradient of
5–95% ACN in water (0.1% TFA) over 50 min at a flow rate of 5 mL/min.
Mass spectrometry of peptoid oligomers and their metal complexes was
performed on a Advion expression CMS mass spectrometer under
electrospray ionization (ESI), direct probe ACN:H2O (95:5), flow rate 0.2
Circular Dichroism. Approximately 500 µL solutions (5 mM in methanol)
of lyophilized peptoids powders were prepared immediately before CD
measurements. CD scans were performed at room temperature at
concentration of 100µM in solution of 80% aqueous methanol. The
spectra were obtained by averaging 4 scans per sample in a fused quartz
cell (path length = 0.1 cm). Scans were performed over the 300 to 190
nm region at a step of 1nm (scan rate=1 sec/step).
ml/min and on
a Waters LCT Premier mass spectrometer under
electrospray ionization (ESI), direct probe ACN:H2O (70:30), flow rate 0.3
ml/min. UV measurements were performed using an Agilent Cary 60 UV-
Vis spectrophotometer, a double beam, Czerny-Turner monochromator.
CD measurements were performed using
a
circular dichroism
Synthesis of Cu2+ complexes for EPR experiments. Copper
complexes for EPR were prepared in methanol (0.5mL) by addition of 1.1
equivalent of copper acetate 10 mM in methanol solution to peptoids 7P1
(4.86 mg, 4.20 µmol), 7P2 (4.87 mg, 4.22 µmol), 7P3 (4.86 mg, 4.20
µmol), 7P4 (4.88 mg, 4.22 µmol), 7P5 (5.18 mg, 4.48 µmol), 7P6 (4.67
mg, 4.04 µmol), 7P7 (4.8 mg, 4.16 µmol) and 7P8 (4.01 mg, 3.2 µmol).
The mixtures were shacked for 1 hour. Precipitates were obtained after
adding an aqueous solution of NH4PF6 (200 µl, 1M), shaking for 30 min
and centrifugation. Precipitates were washed twice with water and
lyophilized overnight. 7P1Cu was obtained in 85% yield (5.27 mg),
7P2Cu 91.0% yield (4.63 mg) and 7P3Cu 80.0% yield (4.87 mg) 7P4Cu
was obtained in 81.7% yield (5.21 mg), 7P5Cu 93.2% yield (6.30 mg),
7P6Cu was obtained in 77% yield (3.1 mg), 7P7Cu 80% yield (3.32 mg)
and 7P8Cu 82.5% yield (3.46 mg).
spectrometer Applied Photophysics chirascan. EPR spectra were
recorded on a Bruker EMX-10/12 X-band (ν=9.4 GHz) digital EPR
Spectrometer. Spectra processing and simulation were performed with
Bruker WIN-EPR and SimFonia Software. Data processing was done
with KaleidaGraph software.
Synthesis of the Peptoid Oligomers. Solid-phase synthesis of peptoid
oligomers was performed in fritted syringes on Rink amide resin using a
variation of a previously reported peptoid sub-monomer protocol.2 In a
typical oligomer synthesis, 100 mg of resin with a loading level of 0.83
mmol·g-1 was swollen in 4 mL of dichloromethane (DCM) for 40 min.
Following swelling, the Fmoc protecting group was removed by treatment
with 2 mL of 20% piperidine in dimethylformamide (DMF) for 20 min.
After de-protection and after each subsequent synthetic step, the resin
was washed three times with 2 mL of DMF, one minute per wash.
Peptoid synthesis was carried out with alternating bromoacylation and
amine displacement steps. For each bromoacylation step, 20 equiv.
bromoacetic acid (1.2 M in DMF, 8.5 mL g-1 resin) and 24 equiv. N,N′-
diisopropylcarbodiimide (neat, 2 mL g-1 resin ) were added to the resin,
and the mixture was agitated for 20 min. After washing, 20 equiv. of the
required amine (1.0 M in DMF) were added to the resin and agitated for
20 min. This two-step addition cycle was modified as follows (For 100 mg
resin): after incorporation of 8-hydroxy-2-quinolinemethylamine, 0.17 ml
Acknowledgements
The research leading to these results has received funding from
the European Union's
–
Seventh Framework Program
(FP7/2007-2013) under grant agreement n° 333034-MC--MF
STRC AND FCN. The authors thank Mrs. Larisa Panz for her
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10.1002/chem.201704497
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(b) Schettini, R.; De Riccardis, F.; Della Sala, G.; Izzo, I. J. Org. Chem.
2016, 81, 2494-2505.
assistance with the various MS measurements and Dr. Boris
Tumanskii for his assistance with the EPR measurements. Maria
Baskin thanks the Schulich foundation and the Gutwirth
foundation for her PhD fellowship.
[12] J. Sun, R. N. Zuckermann, ACS Nano, 2013, 7, 4715-4732.
[13] Gorske, B. C.; Stringer, J. R.; Bastian, B. L.; Fowler, S. A.; Blackwell, H. E.
J. Am. Chem. Soc. 2009, 131, 16555-16567.
[14] Caumes, C.; Roy, O.; Faure, S.; Taillefumier, C. J. Am. Chem. Soc. 2012,
134, 9553-9556.
Keywords: peptoid • peptide • helix • metal coordination •
[15] (a) J. R. Stringer, J. A. Crapster, I. A. Guzei, H. E. Blackwell, J. Am.
Chem. Soc. 2011, 133, 15559-15567; (b) J. A. Crapster, I. A. Guzei, H. E.
Blackwell, Angew. Chem. Int. Ed. 2013, 52, 5079-5084.
secondary structure
[16] (a) O. Roy, C. Caumes, Y. Esvan, C. Didierjean, S. Faure, C. Taillefumier,
Org. Lett., 2013, 15, 2246-2249; (b) O. Roy, G. Dumonteil, S. Faure, L.
Jouffret, A. Kriznik, C. Taillefumier, J. Am. Chem. Soc., 2017, DOI:
7b07475.
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Lieby Zborovsky, Alisa Smolyakova,
Maria Baskin, Galia Maayan.
Page No. – Page No.
A Pure Polyproline Type I-like Peptoid
Helix via Metal Coordination
Cu2+ binding to N-hydroxyquinoline ligands incorporated within a peptoid oligomer
significantly altered its secondary structure as suggested by CD spectroscopy: the
spectra of the unbound peptoid, which reflects a mixture of PP-I and PP-II helices,
transformed upon Cu2+ binding to resemble the spectra of a pure PP-I helix. Studies
on a series of peptoids revealed a battle between two driving forces for folding –
coordination geometry and sequence.
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This article is protected by copyright. All rights reserved.