Structural Properties and Stereochemically Distinct Folding Preferences of 4,5-cis and trans-Methano- L -Proline Oligomers: The Shortest Crystalline PPII-Type Helical Proline-Derived Tetramer

Article abstract of DOI:10.1002/anie.201506208

The synthesis, structural properties, and folding patterns of a series of L-proline methanologues represented by cis- and trans-4,5-methano-L-proline amides and their oligomers are reported as revealed by X-ray crystallography, circular dichroism measurements, and DFT calculations. We disclose the first example of a crystalline tetrameric proline congener to exhibit a polyproline II helical conformation. Experimental evidence of PPII-type helical arrangement (both in solution and in the solid state) of cis-4,5-methano-L-proline oligomers is supported by theoretical calculations reflecting the extent of n→π? stabilization of the trans-amide conformation.

Full text of DOI:10.1002/anie.201506208

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International Edition: DOI: 10.1002/anie.201506208
German Edition: DOI: 10.1002/ange.201506208
Proline Isomerization
Structural Properties and Stereochemically Distinct Folding
Preferences of 4,5-cis and trans-Methano-l-Proline Oligomers: The
Shortest Crystalline PPII-Type Helical Proline-Derived Tetramer
Gilles Berger, Miguel Vilchis-Reyes, and Stephen Hanessian*
Abstract: The synthesis, structural properties, and folding
patterns of a series of l-proline methanologues represented by
cis- and trans-4,5-methano-l-proline amides and their oligo-
mers are reported as revealed by X-ray crystallography,
circular dichroism measurements, and DFT calculations. We
disclose the first example of a crystalline tetrameric proline
congener to exhibit a polyproline II helical conformation.
Experimental evidence of PPII-type helical arrangement (both
in solution and in the solid state) of cis-4,5-methano-l-proline
oligomers is supported by theoretical calculations reflecting the
Figure 1. a) Cis–trans isomerism of the Xaa-Pro amide bond. b) Impor-
tant dihedrals for proline conformations.
extent of n!p* stabilization of the trans-amide conformation.
P
roline residues are of high importance in the conforma-
tional heterogeneity of proteins, notably by the presence of
both cis and trans conformations of their peptide bonds.
Indeed, the cyclic nature of proline imposes structural
constraints, which comprise a higher frequency of cis peptide
bonds (approx. 5%) compared to other amino acids (less than
0.1%).[1–4] Moreover, cis–trans isomerization of proline amide
bonds are involved in many biological processes, such as
ligand recognition, protein folding, and ligand-gated ion
channel opening.[5–10]
Both in the solid state and in solution, poly(Pro) peptides
adopt helical conformations, known as polyproline I (PPI)
and polyproline II (PPII). PPI is a compact, right-handed
helix with all its residues adopting a cis-amide conformation
with characteristic f and y angles around À758 and + 1608,
and associated with a helical pitch of 5.6 Š. PPII exists in
a looser, left-handed helix of trans-amide bonded residues
with dihedral angles f and y around À758 and + 1458; the
pitch of the helix is around 9.4 Š, making it less compact than
the PPI helix.[15–18]
PPII is known to occur in unordered peptides, globular
proteins, the structural protein collagen, and short oligopep-
tides.[18–25] Despite its name, the PPII-type helical arrange-
ment can also be found in poly(Glu), poly(Lys), poly(Ala)
peptides, and in many other regions of proteins.[26] Local PPII-
type secondary structures have been shown to be of crucial
importance in protein structure and function.[19] PPII-type
helicity is favored in aqueous media,[21,27,28] whereas a PPI
conformation is more stable in the absence of coordinating
water molecules.[29]
Previous studies from our laboratories have shown that
the pyrrolidine ring in cis- and trans-4,5-methanoprolines is
essentially planar compared to proline itself, as evidenced by
single crystal X-ray crystallography.[30] We surmised that the
conformational constraint imparted by the fused cyclopro-
pane ring could affect the properties of prolylamides in
several ways. For example, changing the dihedral angles could
profoundly affect the hybridization level of the nitrogen atom
(planar or pyramidal), with consequences reflected in the cis–
trans isomerism of the amide bond. We were also intrigued by
the prospects of replacing proline residues in known drugs by
cis- and trans-4,5-methanoprolines to probe the spatial
requirements of the pyrrolidine ring within the active site of
a relevant enzyme. Indeed, the cis- and trans-4,5-methano-l-
proline counterparts of the antihypertensive drug captopril,
an inhibitor of the angiotensin converting enzyme (ACE),[31]
Apart from the cis–trans conformations of the Xaa-Pro
peptide bonds, the pyrrolidine ring of proline residues can
adopt either a Cg-endo or Cg-exo pucker conformation.
Indeed, Cg experiences large out-of-plane displacement, and
this ring-puckering seems to be correlated to the trans/cis
amide ratio (KT/C).[3,11–13] Highly populated Cg-exo puckers
exhibit high KT/C, whereas high populations of Cg-endo
puckers are associated with lower KT/C values.[14] Among
other parameters, these observations are rationalized by
greater n!p* hyperconjugative delocalization in exo-puck-
ered proline. Relevant dihedral angles and conformations
that define the structural properties of proline are depicted in
Figure 1.
[*] Dr. G. Berger, Dr. M. Vilchis-Reyes, Prof. Dr. S. Hanessian
Department of Chemistry, UniversitØ de MontrØal
Station Centre-Ville, C.P. 6128, Montreal, QC, H3C 3J7 (Canada)
E-mail: stephen.hanessian@umontreal.ca
Dr. G. Berger
Faculty of Pharmacy, Laboratory of Pharmaceutical Chemistry,
UniversitØ Libre de Bruxelles
Campus Plaine CP205/5, UniversitØ Libre de Bruxelles,
Bd du Triomphe, 1050 Brussels (Belgium)
Supporting information for this article, including synthetic proce-
dures, compound characterization, and crystallographic and com-
putational data, is available on the WWW under http://dx.doi.org/10.
1002/anie.201506208.
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were equally active nm inhibitors.[32] In another context,
conformationally constrained indolizinones containing
a fused cyclopropane enhanced the antibacterial activity of
ceftazidime, most likely acting as an inhibitor of a b-
lactamase.[33] More recently, the marketed antidiabetic drug
Onglyza (saxagliptin), a dipeptidyl peptidase-4 (DPP4) inhib-
itor, contains a 4,5-methano-l-prolylnitrile as an important
core subunit.[34,35] Incorporation of the 4,5-fused cyclopropane
ring in saxagliptin was critical in prolonging the half-life of the
drug compared to the l-prolylnitrile prototype.
Herein, we report the synthesis and structural properties
of cis- and trans-4,5-methano-l-proline amides and oligomers
(Figure 2) as revealed by X-ray diffraction (XRD), circular
Figure 2. Cis- and trans-4,5-methano-l-prolines and their oligomers
used in the present study.
Figure 3. a) Single-crystal structures of cis/cis, trans/trans, and trans/cis
N-Boc-MPro-MPro-CO2Et dimers. b) X-ray of trimeric N-Boc-cis-4,5-
methano-l-proline ethyl ester.[41]
dichroism (CD), and density functional theory (DFT) calcu-
lations. We also disclose the shortest example of a crystalline
tetrameric proline congener to exhibit a polyproline II helical
conformation. We hasten to add that whereas tetrameric
prolines have been reported, their capacity to adopt a PPII
helical conformation is not conclusive.[36,37]
The cis- and trans-4,5-methano-l-prolines were obtained
according to previously published procedures (see Supporting
Information for more details).[32,38,39] Monomeric 4,5-meth-
anoprolines were then coupled to obtain their N-Boc di-,
tetra-, and hexamers as ethyl esters, to study their conforma-
tions both in the solid state and in solution, using X-ray
crystallography and CD, respectively.
Obtaining crystalline forms of relatively short oligopro-
lines and the study of their 3-D conformational properties in
the solid state has been the Achilles heel in the quest to obtain
PPII helical motifs. After considerable effort, Wennemers and
co-workers[40] succeeded in obtaining the crystal structure of
the first oligoproline PPII helix comprising only six residues
as the p-bromobenzoyl amide.
strongly suggests that the n!p* stabilization of the trans-
amide conformation is weakened when trans-4,5-methano-l-
prolines are involved. The angles between the amide oxygen
and the acceptor ester carbonyl (bearing the antibonding
orbital) in these structures are found between 84.58 and 97.68,
and differ from the ideal Bürgi–Dunitz trajectory for an n!
p* interaction, which is around 1048.[40,50] Further insight into
these interactions was provided from the DFT structures of
the dimers and natural bond orbital (NBO) analysis (see
below).
We also obtained crystals from the trimeric cis-4,5-
methano-l-proline 2a which further exhibit the progression
of the amide folding pattern to form PPII-like peptide bonds
(Figure 3b).
Encouraged by this result, we were able to crystallize the
tetrameric cis-4,5-methano-l-proline as the methyl ester
hydrochloride salt 3a, and to obtain a crystal structure
showing the expected features of a PPII-type helix (Fig-
ure 4b).
A quasi-C3 symmetry along the helical axis is observed
with a helical pitch of 9.1 Š, so that each methanoproline
residue accounts for about 3 Š. When compared to the
recently published X-ray structure of the oligoproline hexa-
mer by Wennermers and co-workers,[40] the tetrameric cis-4,5-
methano-l-proline helix is very similar (Figure 4c). The
crystals belong to the monoclinic C121 space group (b =
95.898, V= 2848.0 Š3), and the structure was solved by
direct methods to atomic resolution. No inclusion of solvent
was observed, however the assembly is stabilized by a central
double column of chloride ions, facing the ammonium
moieties of two tetramers in a head-to-head fashion.
The folding pattern of the synthesized oligomers into
PPII-type helices in solution was studied by means of circular
dichroism. The characteristic CD signature of a PPII-type
We started our investigations with the study of dimeric cis-
and trans-4,5-methano-l-prolines (Figure 3).
Examination of the crystal structure of the cis/cis dimer 1a
shows structural parameters in agreement with the initiation
of a PPII helix (Figure 3a). The amide adopts a trans
conformation with a y angle around 1658. The distances
between the donor amide oxygen atom and the acceptor ester
carbonyl (d) are substantially less than the sum of their Van
der Waals radii (3.22 Š), supporting the existence of a typical
n!p* interaction, known to stabilize this conforma-
tion.[13,23,29,42–49] Indeed, d1 and d2 are 2.92 and 3.04 Š,
respectively, highlighting strong n!p* delocalization. When
examining the crystal structures either of the trans/trans-
methano-l-proline dimer 1b or the mixed trans/cis-methano-
l-proline dimer 1c, d1 and d2 are still less than the sum of Van
der Waals radii but not as much as in 1a. This observation
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importantly, the trans derivatives
remain disordered under these
conditions (Figure 5).
Subsequent geometry optimi-
zation of the dimers 1a–c at the
DFT
level
(wB97x-D/def2-
TZVP;[54–56] for details see the
Supporting Information) fol-
lowed by NBO analysis[57] pro-
vided the energetic contribution
from the n!p* stabilization of
the trans-amide bonds (Figure 6).
Hyperconjugative delocaliza-
tions arising in the cis-4,5-meth-
ano-l-proline dimer 1a are both
found at about 1.5 kcalmolÀ1,
thereby providing an overall sta-
bilization of the trans-amide con-
formation. However, stabiliza-
tion arising from these delocali-
zations is substantially decreased
for the trans-4,5-methano-l-pro-
line dimer 1b, as one of the two
n!p* energetic contributions
drops to zero. The same observa-
tion is made for the mixed trans-
4,5-methano/cis-4,5-methano
compound 1c, so that dimers
containing trans-4,5-methano-l-
proline moieties experience
decreased stabilization of their
trans-amide conformation. This
could explain the propensity of
Figure 4. a) Tetrameric cis-4,5-methano-l-proline methyl ester hydrochloride 3a. b) Side-view and view
along the helical axis of the crystal structure showing a typical polyproline II helix conformation.
c) Fitting of our tetrameric crystal structure to the hexameric oligoproline from Wennemers and co-
workers.[40] (fitting to heavy atoms only, RMSD=0.34 Š). d) Packing shows central chloride ions
[41]
À
À
interacting with surrounding N H and Ca H bonds. e) Bürgi–Dunitz distances and trajectories.
the
cis-4,5-methano-l-proline
oligomers with trans-amide ori-
entations to arrange in solution
helix, which consists in a strong negative band at 206 nm and
a positive band around 225 nm[15,51—53] can be recognized for
both the all-cis-tetramer 4a and the corresponding hexamer
5a in Figure 5. Clearly, as the numbers of residues increase,
the cis-4,5-methano-l-proline oligopeptides assemble into the
typical PPII-type helix, with as few as four residues. Very
as PPII-type helices, in contrast to the trans-4,5-methano-l-
proline oligomers (see CD in Figure 5).
To verify this hypothesis for larger and more relevant
structures, tetramers 3a (the crystalline cis-4,5-methano-l-
proline tetramer) and 3b (its all-trans-4,5-methano counter-
part) were DFT-optimized. NBO analysis interestingly shows
that in the case of the 3a, each residue participates in a strong
n!p* interaction (around 1 kcalmolÀ1 each and a total
contribution of 3 kcalmolÀ1), whereas very limited energetic
effect is gained from these delocalizations in 3b (total
contribution around 0.5 kcalmolÀ1). This leads to a critical
destabilization of the PPII conformation in 3b with respect to
the cis-4,5-methano congener 3a.
As a comparison, the calculations were also run for the l-
proline tetramer. The sum of the calculated n!p* stabiliza-
tion energies for this l-proline tetramer (not shown) were
found to be about 1 kcalmolÀ1 thus lying in between the
,
structures generated from cis-4,5-methano-l-prolines 3a
(ÆDEn!p* = 3.0 kcalmolÀ1) and trans-4,5-methano-l-prolines
3b (ÆDEn!p* = 0.5 kcalmolÀ1).
As previously stated, another dramatic conformational
effect arising upon the introduction of a cyclopropane in the
4,5-position of l-proline is the considerable flattening of the
Figure 5. CD spectra of cis- and trans-4,5-methano-l-proline oligomers
in MeOH/CHCl3 99.9:0.1, showing the typical polyproline II spectrum
for the cis derivatives, whereas the trans isomers remain disordered
under the same conditions. Structures of the tetramers 4a,b and the
hexamers 5a,b are not shown (see the Supporting Information).
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action. Also, a strong correlation is found for the distance
between the donor amide oxygen and the acceptor carbonyl
carbon, as in the cis- 4,5-methano N-acetyl congener, where
the distance is significantly shorter when the interaction is
stronger, an observation already made when comparing
crystal structures of the dimers 1a–c (that is, their Bürgi–
Dunitz distances with calculated n!p* energetic contribu-
tions).
In conclusion, we have demonstrated for the first time that
as few as four cis-4,5-methano-l-proline residues in a tetra-
meric oligopeptide can adopt a PPII helical arrangement in
the solid crystalline state. Geometrical factors affecting the
n!p* interactions between the amide carbonyl and the ester
carbonyl from adjoining residues are crucial parameters for
adopting PPII-type helicity, which is also corroborated by
DFT calculations. This is in agreement with the CD data
showing that cis-4,5-methano-l-proline oligomers form PPII-
type helices, whereas the trans counterparts remain disor-
dered. A number of important applications can be envisaged
based on these results, such as tuning the stability of PPII
regions of peptides by substituting proline residues by their
cis- or trans-4,5-methano congeners. Replacing proline resi-
dues with their 4,5-methanologues can be a useful structural
variation to optimize spatial, stereoelectronic, and conforma-
tional effects in the design of modified drugs and peptides. In
the latter case, one can imagine stabilizing PPII helicity in
peptide or proteins with cis-4,5-methano-l-proline segments,
while destabilizing such secondary structures using trans-4,5-
methano-l-proline counterparts. Studies related to these and
related variations in the nature of the residues are in progress.
Figure 6. NBO analysis of the n!p* interactions arising in the
dimeric structures of cis-4,5-methano-l-proline 1a (left), trans-4,5-
methano-l-proline 1b (right), mixed trans/cis dimer 1c (middle), and
the tetrameric structures 3a and 3b (bottom left and right). Labeling
of stabilization energies DEn!p* (kcalmolÀ1) are from N- to C-terminal
residues. Lone pairs (n electrons) and p antibonding (p* electrons)
NBO are respectively displayed as blue/red and purple/yellow (iso-
value=0.03 au). NBO are not displayed for interactions energies
falling below 0.5 kcalmolÀ1. All of the calculations were run at the
wB97x-D/def2-TZVP level of theory.
Acknowledgements
The authors warmly thank Dr. Michel Simard from the X-ray
Diffraction Laboratory of the UniversitØ de MontrØal. We
also thank Ingrid Chab-Majdalani for technical assistance and
NSERC for financial support. Gilles Berger thanks the ULB-
VUB computing center for providing high performance
computing facilities and useful technical support.
pyrrolidine ring, where it becomes almost planar.[30] Flat-
tening of the pyrrolidine ring in 4,5-methano-l-prolines was
therefore investigated in the light of NBO analysis through
the atomic hybrids forming the bonding orbitals, using N-
acetyl-l-proline ethyl ester, N-acetyl cis- and trans-4,5-
methano-l-proline ethyl esters as model compounds (Sup-
porting Information). Analysis of the results reveal that the
carbon atoms of the cyclopropane ring directly fused to the
Keywords: circular dichroism · methanoproline ·
natural bond orbitals · polyproline
pyrrolidine moiety in cis- and trans-N-acetyl 4,5-methano l-
2
How to cite: Angew. Chem. Int. Ed. 2015, 54, 13268–13272
Angew. Chem. 2015, 127, 13466–13470
À
proline ethyl esters appear to have a stronger sp -type C H
bonding, being almost in the plane of the pyrrolidine ring.
À
Indeed, NBO hybrids of these C H bonds show a balanced
sp3/sp2 character (around sp2.5) in agreement with the flat-
tening of the ring, whereas the same bonding orbitals in the l-
proline equivalent structure involve hybrids with strong sp3
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Received: July 6, 2015
Published online: September 8, 2015
13272 www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 13268 –13272