Characteristic structural parameters for the γ-peptide 14-helix: Importance of subunit preorganization

Article abstract of DOI:10.1002/anie.201101301

All wound up: Crystallographic data for a set of homologous peptides constructed from gabapentin and two to six preorganized γ-amino acid residues (see crystal structure of the longest peptide) allow derivation of characteristic parameters for the γ-peptide 14-helix and establish guidelines for characterizing 14-helical folding. The results suggest that the substitution pattern of a γ-residue has a profound effect on the propensity for 14-helical folding.

Full text of DOI:10.1002/anie.201101301

DOI: 10.1002/anie.201101301
Peptide Structures
Characteristic Structural Parameters for the g-Peptide 14-Helix:
Importance of Subunit Preorganization**
Li Guo, Weicheng Zhang, Andrew G. Reidenbach, Michael W. Giuliano, Ilia A. Guzei,
Lara C. Spencer, and Samuel H. Gellman*
Dedicated to Professor Ronald Breslow on the occasion of his 80th birthday
The complexity of structure and function among biopolymers
has inspired chemists to extrapolate to non-natural analogues
that are intended to emulate the natural archetypes.[1] b-
Amino acid oligomers, for example, can adopt helix, sheet, or
reverse-turn conformations comparable to the regular secon-
dary structures found in proteins,[2] and b-peptides display a
wider range of secondary structure variation than do a-
peptides.[3,4] Elucidation of b-peptide folding rules has
enabled function-directed design,[5] which has encouraged
exploration of higher amino acids as “foldamer” subunits.[1] g-
Peptides that form discrete helix, sheet, or reverse-turn
secondary structures have been reported,[6–9] but the pace of
g-peptide exploration lags behind that of b-peptides, in part
because of the difficulty of obtaining stereochemically pure
building blocks. The g-peptide 14-helix, defined by 14-atom
Scheme 1. Structures of g-peptides 3–7 (arrows indicate H-bonds in
the crystal structures of 3–7). Bn=benzyl.
=
À
ring i,i + 3 C O···H N H-bonds, was identified through
pioneering efforts of Hanessian et al.[6] and Seebach et al.[7]
and represents the most thoroughly documented g-peptide
secondary structure. Nevertheless, just one atomic-resolution
crystal structure containing this helix has been reported.[9,10]
Here we report a set of crystal structures that allow the
derivation of characteristic parameters for the g-peptide 14-
helix, which was not previously possible. Furthermore, the
crystallographic data establish proton NOE patterns that are
definitive for 14-helical folding in solution. Use of a con-
formationally constrained g-amino acid (2, Scheme 1)[11] was
crucial for the generation of these structural data.
is part of an amide group (e.g., at the C terminus of a peptide)
often leads to epimerization by transient azalactone forma-
tion, while epimerization is suppressed when the amino group
is part of a urethane (e.g., Boc). We find a complementary
situation with g-peptides constructed from 2: the N-Boc
derivative of 2 is highly prone to g-lactam formation under
standard coupling conditions, and this side reaction is sup-
pressed when the backbone nitrogen atom is part of an
amide.[12] Therefore, g-peptides 3–7 were constructed by
stepwise extension starting from the N terminus. A gabapen-
tin residue was placed at the N terminus because N-Boc-
gabapentin is not prone to g-lactam formation during
coupling reactions.
We used solution-phase methods to prepare a series of g-
peptides, 3–7 (Scheme 1), which contain a tert-butoxycarbonyl
(Boc)-protected residue derived from commercially available
gabapentin (1) at the N termini and cyclically constrained
residues derived from g-amino acid 2 at all other positions.
Stepwise synthesis of a-peptides typically proceeds from
C terminus to N terminus, because carboxy activation of a-
amino acid derivatives in which the backbone nitrogen atom
g-Amino acid 2 was selected as the principal component
of these oligomers, because protected forms are readily
available from butanal and 1-nitrocyclohexene,[11] and
because the ring constraint and stereochemistry are expected
to promote a gauche+,gauche+ torsion-angle sequence about
À
À
[*] Dr. L. Guo, W. Zhang, A. G. Reidenbach, M. W. Giuliano,
Dr. I. A. Guzei, L. C. Spencer, Prof. S. H. Gellman
Department of Chemistry, University of Wisconsin, Madison
Madison, WI 53706 (USA)
the Ca Cb and Cb Cg bonds, which computational analysis
suggests to be conducive to 14-helix formation.[13] In contrast,
the diastereomeric building block with a trans-disubstituted
cyclohexane ring[11] is expected to favor a gauche+,anti
torsion-angle sequence. The synthetic route that provides 2
enables placement of a wide variety of side chains at the a-
position, and it seems likely that the behavior observed with
an ethyl group at this position will prove to be representative
of other unbranched side chains.
Fax: (+1)608-265-4534
E-mail: gellman@chem.wisc.edu
[**] This research was supported by the NSF (CHE-0848847). NMR
spectrometers were purchased with partial support from the NIH
and NSF.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201101301.
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Communications
Table 1: Average torsion angles[a] from 14-helical segments.
g-Peptide
4–7
Residue
f
q
z
y
gabapentin[b]
98.6 À67.2
À76.7
82.5
g-AA[c]
À154.5
60.2
59.5 À126.8
Seebach et al.[9] g-AA[d]
g-AA(4)[e]
140.4 À67.1
À54.6
133.6
51.0
109.1
174.6 À178.6
[a] Backbone torsion angles in g-amino acid residues are defined in
Scheme 1. [b] Average backbone torsion angles of gabapetin residues in
4–7. [c] Average backbone torsion angles of g-amino acid residues
derived from 2 in 4–7, excluding the C-terminal residue in each case (14
independent g-amino acid residues from 4–7 were used to generate the
torsion-angle averages; see the Supporting Information). [d] Average
backbone torsion angles of the first three g-amino acid residues in the
crystal structure of the four-residue g-peptide reported in Ref. [9].
[e] Torsion angles of the C-terminal residue in the crystal structure of the
four-residue g-peptide reported in Ref. [9].
prevents incorporation of the C-terminal residue into the 14-
helical H-bond pattern. Similarly, the C terminus of the
previously described tetramer[9] is an ester, and in this case the
C-terminal residue displays torsion angles that deviate
dramatically from those required for the 14-helix: the z and
q torsion angles (Scheme 1) are anti rather than gauche for
this residue. Among 4–7, only minor variations in the
backbone torsion angle are observed between the C-terminal
residue and other residues derived from 2, a trend that
presumably arises because the cyclic constraint of 2 confers
strong conformational preorganization, in contrast to the
modest conformational preference provided by an acyclic
stereochemical control strategy.[9]
Standard methods for deriving helical parameters such as
the number of residues per turn (n), rise per turn (pitch; p),
rise per residue (d), and radius (r) require atomic-resolution
structures containing segments of four contiguous helical
residues.[14] Hexa-g-peptide 6 and hepta-g-peptide 7 provide
the first opportunities for such analysis among g-peptides,
with one four-residue segment in 6 and two such segments in
7. The helical parameters deduced from these three segments
are very similar to one another, as shown in Table 2.
Figure 1. Crystallographic data. a) Crystal structures of 3–7. b) Stereo-
Table 2: 14-Helical parameters from structures of 6 and 7.
view of the 14-helical segment of 7 (N-terminal gabapentin residue not
shown). c) View along the helix axis of the 14-helical segment of 7.
Orange: Boc-protected gabapentin residue, green: residues derived
from 2, red: O, blue: N.
Peptide
n
p [ꢀ]
d [ꢀ]
r [ꢀ]
hexamer 6
heptamer 7
2.5
2.6
2.5
5.4
5.5
5.5
2.1
2.1
2.2
2.9
2.9
2.9
average
2.5
5.5
2.1
2.9
In the crystal structures of 4–7 (Figure 1), the segments
derived from 2 display the 14-helical conformation. All
possible 14-atom-ring H-bonds are formed within each of
these segments. This data set permits us to derive robust
averages for the backbone torsion angles of a g-amino acid
residue involved in a canonical 14-helix (Table 1). These
average values correspond well to relevant torsion angles in
the only reported crystal structure of a helical g-peptide, a
tetramer.[9] Our averages do not include the C-terminal
residue from 4–7. The C terminus itself is an ester in each
case, and the lack of an H-bond donor at this position
The new structural data for segments derived exclusively
from 2 allow us to identify H–H distances that are expected to
give rise to medium-range nuclear Overhauser effects
(NOEs) in the g-peptide 14-helical conformation. In general,
NOEs between protons that are distant from one another in
terms of covalent connectivity, specifically, protons that are
not from the same residue or from sequentially adjacent
residues, provide strong evidence for population of compact
conformations in solution. The crystallographic data indicate
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However, no C9 H-bond across a residue derived from 2 is
observed in the crystal structures of larger g-peptides 4–7,
where 14-atom H-bonding becomes possible in the segments
composed of 2. We interpret the dominance of C14 H-bonding
among 4–7 as strong evidence that the residue derived from 2
has an intrinsic preference for the 14-helical conformation. In
contrast, our data indicate that the gabapentin residue has a
strong preference for the C9 H-bond: even when the
gabapentin residue could participate in a 14-helix, as in 4–7,
this residue consistently forms the shorter-range H-bond.
Previously we noted that adoption of compact and specific
conformations by unnatural peptidic oligomers requires
subunits that disfavor H-bonds between nearest-neighbor
backbone amide groups.[16]
Our conclusions regarding gabapentin conformational
preferences are consistent with those suggested by crystal
structures of short gabapentin-containing peptides, many of
which feature the C9 H-bonding pattern.[17] This purely local
gabapentin folding pattern does not necessarily lead to a
regular secondary structure, as illustrated by the crystal
structure of a gabapentin tetramer, in which the torsion angles
within the C9 rings vary irregularly along the sequence.[8g] In
contrast, NMR spectroscopic analysis of g-peptide oligomers
containing g4-amino acid residues (i.e., g residues with a side
chain at the carbon next to nitrogen) bearing a bulky side
chain suggest formation of a regular 9-helix.[8h] Other g-
peptide conformations containing multiple C9 H-bonded rings
have been reported as well.[8f,i,j]
Scheme 2. H–H distances in the crystal structures of g-peptides 4-7,
corresponding to medium-range NOE patterns, expected to be charac-
teristic of g-peptide 14-helix formation in solution.
six types of H–H juxtapositions, involving protons on the
backbone or on the first carbon atom of a side chain, that
should give rise to non-sequential NOEs characteristic of the
14-helix (Scheme 2 and Table 3). This analysis reveals that
Table 3: Average H–H distances in crystal structures of 4–7 correspond-
ing to medium-range NOE patterns expected to be characteristic of g-
peptide 14-helix formation in solution.
NOE type
Number of measurements
Distance [ꢀ]
CgH(i) to CaH(i+2)
CgH(i) to NH(i+2)
CgH(i) to Ca(b’)H(i+2)
CgH(i) to NH(i+3)
CbH(i) to NH(i+3)
9
9
9
6
6
9
2.6Æ0.4
2.7Æ0.1
3.4Æ0.4
4.0Æ0.1
4.4Æ0.2
4.0Æ0.1
Cg(b’)H(i) to NH(i+2)
Atomic-resolution data from a series of 14-helical g-
peptides have enabled us to generate definitive structural
parameters for this secondary structure. Furthermore, the
crystallographic data identify key backbone proton NOE
patterns that should be manifested upon 14-helical folding in
solution. These benchmarks are useful both for evaluating
previous NMR spectroscopy studies[6,7,15] and for guiding
future conformational explorations. This level of analysis was
not previously possible among g-peptides; the conformational
preorganization inherent in g-amino acid residues derived
from 2 presumably contributes to the high propensity of
oligomers 3–7 to crystallize and therefore to our success in
acquiring multiple 14-helical structures. Atomic-resolution
conformational analysis of foldamers containing preorgan-
ized b-amino acid residues has provided a foundation for
structure-based designs of b- and a/b-peptides with specific
functions,[5,18] and the conformational insights provided here
should have comparable value for function-based design of g-
peptides.
CgH(i)–CaH(i+2), CgH(i)–NH(i+2), and CgH(i)–Ca(b’)H(i+2)
NOE patterns should be particularly useful, since these H–H
distances are between 2.5 and 3.5 ꢀ in the crystal structures.
(The designation Ca(b’)H indicates a proton on the first carbon
atom (b’) of a side chain attached to the backbone a-carbon
atom.) NMR spectroscopy data reported by Hanessian et al.[6]
for two g-peptide hexamers include numerous NOEs of these
types, which strongly support 14-helix formation. Our crys-
tallographic data identify three additional H–H distances
between 4.0 and 4.5 ꢀ, which might give rise to weak NOEs:
CgH(i)–NH(i+3), CbH(i)–NH(i+3), and Cg(b’)H(i)–NH(i+2).
(Cg(b’)H indicates a proton on the first carbon atom (b’) of a
side chain attached to the backbone g-carbon atom.) NMR
spectroscopy data reported by Seebach et al.[7,15] are largely
consistent with the data in Table 3, but these studies also
revealed NOEs that can now be recognized as inconsistent
with the 14-helix. One six-residue g-peptide displayed a
strong Cg(b’)H(i)–NH(i+3) NOE,[7] but the crystallographic
data indicate that this H–H distance is typically (5.3 Æ 0.2) ꢀ
in the 14-helix (six measurements). Another six-residue g-
Received: February 21, 2011
Published online: May 12, 2011
peptide displayed
a medium-intensity CgH(i)–CaH(i+3)
NOE,[15] but the crystallographic data indicate an H–H
distance of (5.9 Æ 0.2) ꢀ (six measurements). The non-14-
helical NOEs suggest conformational heterogeneity for these
g-peptides in solution.
Keywords: foldamers · helical structures · NMR spectroscopy ·
.
nuclear Overhauser effect · peptides
The gabapentin residue at the N terminus of 3–7 forms a
=
À À
nine-atom-ring H-bond (C O(i) H N(i+2)) in each crystal
structure. Trimer 3 has a second C9 H-bond, across the central
residue, which suggests that this H-bond pattern is energeti-
cally reasonable for g-amino acid residues derived from 2.
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