Differential Effects of β3- versus β2-Amino Acid Residues on the Helicity and Recognition Properties of Bim BH3-Derived α/β-Peptides

Article abstract of DOI:10.1002/anie.201806909

Oligomers containing α- and β-amino acid residues (α/β-peptides) have been shown to mimic the α-helical conformation of conventional peptides when the unnatural residues are derived from β³-amino acids or cyclic β-amino acids, but the impact of incorporating β² residues has received little attention. The effects of β² residues on the conformation and recognition behavior of α/β-peptides that mimic an isolated α-helix were investigated. This effort has focused on 26-mers based on the Bim BH3 domain; a set of isomers with identical α/β backbones that differ only in the placement of certain side chains along the backbone (β³ vs. β² substitution) was compared. Circular dichroism data suggest that β² residues can be helix-destabilizing relative to β³ residues, although the size of this effect seems to depend on side chain identity. Binding data show that β³→β² substitution at sites that contact a partner protein, Bcl-x_L, can influence affinity in a way that transcends effects on helicity.

Full text of DOI:10.1002/anie.201806909

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Accepted Article
Title: Differential Effects of β³- vs. β²-Amino Acid Residues on the
Helicity and Recognition Properties of Bim BH3-Derived α/β-
Peptides
Authors: Geoffrey A Eddinger and Samuel H Gellman
This manuscript has been accepted after peer review and appears as an
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201806909
Angew. Chem. 10.1002/ange.201806909
Link to VoR: http://dx.doi.org/10.1002/anie.201806909
http://dx.doi.org/10.1002/ange.201806909

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Differential Effects of β3- vs. β2-Amino Acid Residues on the
Helicity and Recognition Properties of Bim BH3-Derived α/β-
Peptides
Geoffrey A. Eddinger and Samuel H. Gellman*
Abstract: Oligomers containing - and -amino acid residues (“/-
peptides”) have been shown to mimic the -helical conformation of
conventional peptides when the unnatural residues are derived from
3-amino acids or cyclic -amino acids, but the impact of
incorporating 2 residues has received little attention. We have
investigated the effects of 2 residues on the conformation and
recognition behavior of /-peptides that mimic an isolated -helix.
This effort has focused on 26-mers based on the Bim BH3 domain;
we have compared a set of isomers with identical / backbones
that differ only in the placement of certain side chains along the
backbone (3 vs. 2 substitution). Circular dichroism data suggest
that 2 residues can be helix-destabilizing relative to 3 residues,
although the size of this effect seems to depend on side chain
identity. Binding data show that 3 → 2 substitution at sites that
contact a partner protein, Bcl-xL, can significantly influence affinity in
a way that transcends effects on helicity. Overall, these results
suggest that 2-amino acids are useful complements to isomeric 3-
amino acids for tuning the recognition properties of /-peptides.
have received little attention.30–32 This disparity arises because
many protected 3-amino acids are commercially available, but
most protected 2-amino acids must be synthesized.33 We
envisioned that 2 residues might be worthy of consideration, as
alternatives to isomeric 3 residues, at positions that make direct
contact with a binding partner. In such situations, the difference
in side chain positioning for 2 vs. 3 residues might significantly
influence /-peptide recognition properties.
Figure 1. Generic structures of -amino acid residues employed in this work.
A generic L- residue is shown for comparison.
We selected binding to the protein Bcl-xL as a model
system for evaluating the impact of interchanging 3 and 2
residues on the affinity of /-peptides for a partner. Bcl-xL is an
anti-apoptotic member of the Bcl-2 family, which includes Bcl-2
itself, Mcl-1, and other members.34 The natural ligands for Bcl-xL
are pro-apoptotic proteins that contain a Bcl-2 homology 3 (BH3)
domain, which adopts an -helical conformation upon binding to
an anti-apoptotic partner protein. Identification of ligands for
these binding sites has been widely pursued for medicinal
purposes;35 a small-molecule antagonist of BH3 domain binding
to Bcl-xL is an anti-cancer drug.36 Insights and techniques that
have emerged from extensive studies in this area make binding
to anti-apoptotic Bcl-2 family members a useful model system
for evaluation of α-helix mimicry strategies.10,16,37,38 The /-
peptides discussed here are based on previously reported 26-
mer -peptide 1 (Figure 2),39 which encompasses the BH3
domain of the pro-apoptotic protein Bim. Peptide 1 contains four
key hydrophobic residues (designated h1-h4) that are buried
upon binding to the BH3-recognition cleft of Bcl-xL. /-Peptide 2
is an analogue that retains the side chain sequence of 1 but
features an  pattern in the backbone. All four of the
key hydrophobic side chains (h1-h4) are contributed by 3
residues in 2. /-Peptide 2 displays modest affinity for Bcl-xL
Mimicking the information encoded in the surface of a folded
polypeptide with an unnatural molecule represents a substantial
design challenge. Such mimics may antagonize specific protein-
protein or protein-nucleic acid interactions or engage
polypeptide-activated receptors.1–3 These functional goals are
often achieved with engineered peptides or proteins based on a
conventional poly--amino acid backbone, but peptides are
susceptible to proteolysis and adverse immunological
recognition, which can limit utility in vivo.4 This situation has
inspired many efforts to develop unnatural oligomeric scaffolds
that can mimic informational surfaces displayed by poly--
peptides.5–8 The regularity of -helical secondary structure and
the frequency with which -helices are found at protein-protein
interfaces9 have engendered diverse strategies for -helix
mimicry,10–18 many involving unnatural oligomeric backbones.19–
26
One approach involves the use of -amino acids as building
blocks for -helix mimics, either exclusively or in combination
with other types of amino acids.26–29
Our group has developed strategies for arranging  and
residues in patterns that enable the resulting oligomers (“/-
peptides”) to mimic the structure and function of specific -
helices.29 To date, these efforts have focused on oligomers
containing 3-amino acid residues (Figure 1) and/or cyclic -
amino acid residues. 2-Amino acid residues, which differ from
3 residues only in the placement of the side chain (Figure 1),
according to
a competition fluorescence polarization (FP)
assay40 (Ki = 190 nM for 2 vs. Ki < 0.7 nM for 1). This situation is
ideal for comparing isomeric /-peptides in which some or all
side chains buried against Bcl-xL (h1-h4) are projected by 2
rather than 3 residues, because the competition FP assay can
detect increases or decreases in affinity relative to that
manifested by 2.
[*]
G. A. Eddinger and Prof. S. H. Gellman
Department of Chemistry
University of Wisconsin-Madison
1101 University Avenue, Madison, WI 53706
E-mail: gellman@chem.wisc.edu
/-Peptides 3-10 are isomers of 2 in which a subset of the
original 3 residues at positions h1-h4 has been replaced with
isomeric 2 residues. One of the protected 2-amino acids
required for these peptides, Fmoc-2-hIle, is not commercially
Supporting information for this article is given via a link at the end
of the document
This article is protected by copyright. All rights reserved.

10.1002/anie.201806909
Angewandte Chemie International Edition
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available and was prepared by a previously described synthetic
method that features an asymmetric Mannich reaction.41
Competition FP data for binding to Bcl-xL revealed that Ki varied
by more than 100-fold among 2-10 (Figure 2); thus, this
interaction is quite sensitive to the difference in side chain
position between 3 and 2 residues. Single 3 → 2 substitution
at h1 or h2 (3 or 4) caused little change in affinity, but
substitution at h3 or h4 (5 or 6) diminished affinity. We explored
combinations of 3 → 2 substitutions among h1-h4 (7-10) to
determine whether the impact of these changes would be
additive. Placing 2 residues at h1 and h2 (7) resulted in a ~6-
fold increase in affinity relative to 2; 7 displayed the highest
affinity for Bcl-xL among the /-peptides in this series. Placing
2 residues at h1 and h3 (8) caused a 17-fold decrease in affinity
relative to the all-3 case (2). /-Peptide 9 contains 2 residues
at h1, h2, and h3 and displayed an affinity for Bcl-xL
indistinguishable from that of 2, while inclusion of the fourth 2
residue at h4 (10) eroded affinity. These findings suggest that
the effects of multiple 3 → 2 substitutions on affinity for Bcl-xL
are roughly additive. The Bim BH3 domain (1) binds tightly to
Mcl-1, but /-peptide 2 does not bind detectably to Mcl-1
(Figure S6). /-Peptides 3-10 also did not bind to Mcl-1 (Figure
S6).
Binding of /-peptides to Bcl-xL and related proteins
requires that these oligomers adopt an -helix-like conformation,
as documented in multiple co-crystal structures involving BH3-
mimetic peptides that contain 3 residues.38,43–46 We wondered
whether isomeric 2 and 3 residues differ in helix-forming
propensity, because this factor could influence affinity for Bcl-xL
among 2-10. The conformational behavior of /-peptides that
contain 2 residues has received little attention to date. In the
two pertinent examples, Tavenor et al. and Fisher et al.
measured the helix propensity of 3 and 2 residues using the
GB1 tertiary motif and a parallel coiled-coil thioester exchange
system, respectively.31,47 Tavenor et al. concluded that there
was no significant difference in helix propensity between the
isomeric 3 and 2 residues they studied, while Fisher et al.
measured a small decline in helix propensity for 2 residues
relative to their 3 analogues. The Bim BH3 sequence we have
studied forms an isolated -helix, allowing us to address the
impact of 3 → 2 substitution on helicity in the absence of any
tertiary context.
Figure 3. Far-UV CD spectra of /-peptides 2-10 in 50% MeOH, 50% 10 mM
TBS, pH 7.5 (v/v). Peptide concentrations range from 75 to 95 M. CD signal
is corrected for sequence length and concentration (i.e., the vertical axis units
are mean residue ellipticity, []). /-Peptides containing single 2 residues (A)
or multiple 2 residues (B) are compared with parent /-peptide 2.
We used far-UV circular dichroism (CD) to probe for
differences in helical propensity among /-peptides 2-10.
These studies were conducted in a 1:1 mixture of 20 mM
aqueous Tris buffer (TBS), pH 7.5, and methanol. Water-alcohol
mixtures promote helicity among conventional peptides and /-
peptides;48 in addition, the mixed solvent prevented /-peptide
aggregation in the 10-100 M range used for our measurements.
The CD comparison revealed significant variation in the extent of
helix formation among the /-peptides (Figure 3) In the
TBS/methanol solvent, -peptide 1 displayed strong minima
near 220 and 208 nm, characteristic of -helix formation (Figure
S10). /-Peptide 2 displayed a single strong minimum near 207
nm in this solvent (Figure 3A), which is consistent with previous
observations for /-peptides that contain similar  residue
distributions and adopt an -helix-like conformation.38,42,46
Figure 2. Sequences of Bim BH3-derived - and /-peptides with their
corresponding Ki values and apparent helicity. aKi values obtained from
competition FP assays are the average of at least three independent
experiments. Maximum experimental error is approximately 2-fold.
/-Peptides 2-10 share the same backbone and contain
the same complement and sequence of side chains; therefore, it
is noteworthy that these /-peptides display >100-fold variation
in affinity for Bcl-xL. /-Peptide 7 displays the highest selectivity
for Bcl-xL over Mcl-1 (>300-fold) among all Bim BH3-derived /-
peptides reported to date.38,42 Recognition surfaces that contain
-residues allow the position of a side chain to be shifted by the
length of a single carbon-carbon bond, via interconversion of 3
and 2 residues, and the affinity range manifested among 2-10
shows that this variation in side chain position can exert a
substantial impact on recognition properties. Conventional
peptides, comprised entirely of -amino acids, do not allow for
comparably subtle alterations in side chain arrangement.
We established an apparent helicity scale for comparisons
among 2-10 based on mean residue ellipticity at 207 nm ([]207
)
normalized to []207 for 2, which contains exclusively 3 residues
and displayed the strongest minimum (Figure 3). We cannot
quantify the extent of helix formation for 2 based on the CD data,
but the apparent helicity scale provides qualitative insight on
helicity differences within the series. /-Peptides 3, 5, and 6
each contain a single 3 → 2 substitution, and each is
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10.1002/anie.201806909
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indistinguishable from 2 (Figure 3A). In contrast, 4, which also
contains just one 3 → 2 substitution, displays a significantly
less intense minimum relative to 2 and therefore appears to be
less helical than 2. α/β-Peptide 8 contains two 3 → 2
substitutions that do not individually affect helicity, but 8 appears
to be moderately less helical relative to 2 (Figure 3B). A more
substantial decline is observed for 7, which also contains two 3
→ 2 substitutions. /-Peptides 9 and 10, with three and four 3
→ 2 substitutions, respectively, are significantly less helical
than 2, but 9 and 10 are comparable to 7.
We anticipated that 2 residues with
S
absolute
configuration would be stereochemically compatible with L--
amino acid residues based on precedent.31,47 We tested this
hypothesis by synthesizing and evaluating /-peptides 11 and
12, which are diastereomers of 3 and 4, respectively, that
contain single (S)-2→(R)-2 substitutions (Figure 4A). CD data
obtained in 1:1 TBS/methanol show that 11 and 12 are
significantly less helical than 3 or 4 (Figure 4B). These results
indicate that even a single (R)-2 substitution is detrimental to
right-handed helix formation. Both of the (S)-2→(R)-2
substitutions led to substantial declines in affinity for Bcl-xL
(Figure 4A), further supporting the notion that the S absolute
configuration of 2 residues is the correct choice for mimicry of a
natural -helix.
Taken together, the CD data suggest that 2 residues have
a slightly smaller propensity than 3 residues for participation in
an -helix-like conformation The data also raise the possibility
that side chain identity affects the extent to which 3 → 2
substitution influences helical propensity. This effect is illustrated
by the lower apparent helicity of 4 relative to 3, 5, and 6 (each of
these four /-peptides contains just one 3 → 2 substitution),
and by the lower apparent helicity of 7 relative to 8 (each
contains two 3 → 2 substitutions). The variations in helical
propensity revealed by the CD data do not correlate directly with
variations in affinity for Bcl-xL, as illustrated most clearly by the
behavior of /-peptide 7, which displays the strongest affinity
for Bcl-xL among 2-10 but manifests one of the lowest extents of
helix formation according to the CD data.
We have used the binding of /-peptide variants to a
specific protein partner to ask whether the choice between
isomeric 3- and 2-amino acid residues, which corresponds to a
small difference in side chain placement along the /-peptide
backbone, exerts
a significant impact on the recognition
properties of these compounds. The association between /-
peptide 2 and Bcl-xL provided an excellent opportunity to
address this question, because four of the 3 residue side chains
from 2 are expected to make intimate contacts with Bcl-xL.
Comparisons involving /-peptides 3-10, which are isomers of
2 containing 3 → 2 substitution at one or more of the contact
positions, show that subtle variation in side chain arrangement
leads to >100-fold variation in affinity for Bcl-xL. One of the new
/-peptides, containing two 3 → 2 substitutions, binds to Bcl-
xL with six-fold higher affinity relative to all-3 prototype 2.
Although CD measurements suggest that 3→2 substitution
may modestly diminish the propensity to adopt the helical
conformation necessary for binding, this factor does not appear
to be decisive in terms of /-peptide affinity for Bcl-xL. These
findings suggest that comparing 3 vs. 2 substitution in other
systems should be useful for optimizing /-peptide binding to
specific macromolecular partners.
Acknowledgements
This research was supported by NIGMS (R01GM056414).The
CD instrument was purchased with a supplement to NIH grant
R01GM061238. G. A. Eddinger thanks Shi Liu and Brian Fisher
for their advice on 2-amino acid synthesis and for S. Liu’s
donation of Fmoc-(R)-2-hIle for this study. We thank Dr. Ilia
Guzei for crystallographic analysis.
Conflict of Interest
Figure 4. Effects of (S)-2 → (R)-2 substitution on the affinity and helicity of
Bim BH3-derived /-peptides. The sequences of the two pairs of
diastereomers, 3 + 11 and 4 + 12, along with their Ki values and apparent
helicities are shown (A). The peptides containing single (R)-2 residues bind
significantly less tightly to Bcl-xL (A) and are noticeably less helical (B)
S. H. G. is a cofounder of Longevity Biotech, Inc., which is
pursuing biomedical applications for /-peptides.
Keywords: -helix mimicry • 2-amino acids • circular dichroism
• peptides • protein-protein interactions
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COMMUNICATION
G. A. Eddinger and Prof. S.
H. Gellman *
Page No. – Page No.
Differential Effects of β3-
vs. β2-Amino Acid
Residues on the Helicity
and Recognition
Properties of Bim BH3-
Derived α/β-Peptides
Isomeric 3-to-2-amino acid substitution within a helical /-
peptide exerts significant influence on the peptide’s properties. 2
residues can be helix-destabilizing, but they are also capable of
increasing the peptide’s affinity for a protein binding partner.
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