Structural Insights into the Hydrogen-Bonding and Folding Pattern in Ant-Ant-Pro-Gly Tetrapeptides

Article abstract of DOI:10.1002/ejoc.201700181

In this paper, we provide structural insights into the hydrogen-bonding and folding pattern in Ant-Ant-Pro-Gly tetrapeptides (Ant: anthranilic acid; Pro: proline; and Gly: glycine). Comparison of the C-terminal esters and their amide analogs revealed strikingly different H-bonding networks. Whereas the ester analogs displayed an open structure without terminal H-bonding interactions, the amide analogs showed a completely folded structure. Structural details were revealed by using a combination of X-ray crystal structure studies and NOE-based molecular dynamics (MD) simulation studies.

Full text of DOI:10.1002/ejoc.201700181

A Journal of
Accepted Article
Title: Structural Insights into the Hydrogen-Bonding and Folding
Pattern in Ant-Ant-Pro-Gly Tetrapeptides
Authors: Sachin B Baravkar, Amol S Kotmale, Samir R Shaikh, Rajesh
G Gonnade, and Gangadhar J. Sanjayan
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700181
Link to VoR: http://dx.doi.org/10.1002/ejoc.201700181
Supported by

10.1002/ejoc.201700181
European Journal of Organic Chemistry
FULL PAPER
Structural Insights into the Hydrogen-Bonding and Folding
Pattern in Ant-Ant-Pro-Gly Tetrapeptides
Sachin B. Baravkar,[a] Amol S. Kotmale,[b] Samir R. Shaikh,[c] Rajesh G. Gonnade[c] and
Gangadhar J. Sanjayan*[a]
Abstract: In this paper, we provide structural insights into the
hydrogen-bonding and folding pattern in Ant-Ant-Pro-Gly
tetrapeptides (Ant: anthranilic acid; Pro: proline; and Gly: glycine).
Comparison of the C-terminal ester and their amide analogs
revealed strikingly different H-bonding networks. Whereas the ester
analogs displayed an open structure without having terminal H-
bonding interactions, the amide analogs showed completely folded
structure. Structural details were obtained using a combination of X-
ray crystal structure studies and nOe-based MD simulation studies.
on the individual Ant ring.[10] However, a hybrid (α/β) peptide
having Ant and proline (Pro) showed a turn-like conformation
characterized by a nine-membered intramolecular hydrogen
bonding between the NH of Ant ring and CO group of proline
ring. The steric clash between the nearby Ant and Pro groups in
the dipeptide 2 (Figure 1) caused the two rings to deviate from
planarity, resulting in a folded conformation.[11] It is noteworthy
that six-membered (C6) hydrogen bonding was conspicuously
absent in 2. Strangely, introduction of a glycine (Gly) residue into
2, as shown in tripeptide 3, resulted in the loss of 9-membered
H-bonding, but showed the standard 10-memebered H-bonding
(β-turn), expected from Pro-Gly β-turn inducing motif.[12]
Intriguingly, introduction of proline as a third residue, as in
tripeptide 4, resulted in the loss of both 9- and 6-membered H-
bondings; and only a not-so-common combination of 10- and 11-
membered H-bondings was observed.[13]
Introduction
Folding is a crucial process through which biopolymers fold into
their characteristic three-dimensional compact structures mostly
because of the presence of a collection of non-covalent forces.[1]
Of all non-covalent forces, hydrogen-bonding interaction plays a
vital role in the stabilization of secondary structures. Hydrogen-
bonding interactions assist biopolymers to adopt a well defined
structure - out of millions of other possible conformations and
carry out their specific functions.
Foldamers are conformationally ordered synthetic
oligomers which fold into a specific conformation akin to bio-
macromolecules.[2] Owing to the presence of well-defined three-
dimensional structure, foldamers find applications in biomedical
science,[3] molecular recognition,[4] catalysis[5] and material
chemistry.[6] Hydrogen bonding, along with other conformational
constraints such as torsional angle and π-π stacking, plays a
pivotal role in imparting folded structure to biopolymers.[7]
Peptides having C-terminal esters are sometimes seen devoid of
intramolecular hydrogen bonding at the termini (fraying of
peptide chains), when compared to their amide counterparts.[8]
There are several other contributing factors for peptide chain
fraying which include π-π interactions, NH-π interactions and
bulkiness of the groups at the termini.[9]
Anthranilic acid (Ant) - a constrained aromatic β-amino
acid forms a sheet-like secondary structure in its homo-oligomer
1 (Figure 1) due to the presence of strong intramolecular six-
membered (C6) hydrogen bonding between NH and CO group
[a]
Division of Organic Chemistry, CSIR-National Chemical Laboratory
(CSIR-NCL), Dr. Homi Bhabha Road, Pune 411 008, India. Fax:
+91-020-2590-2629;Tel+91-020-2590-2082;
Figure 1. Some typical examples of H-bonding propensities in anthranilic acid
(Ant)-containing peptides.
E-mail: gj.sanjayan@ncl.res.in; Homepage:
http://nclwebapps.ncl.res.in/gjsanjayan/index.html
Central NMR facility, CSIR-National Chemical Laboratory (CSIR-
NCL), Dr. Homi Bhabha Road, Pune 411 008, India.
Center for Materials Characterization, CSIR-National Chemical
Laboratory (CSIR-NCL), Dr. Homi Bhabha Road, Pune 411 008,
India.
[b]
[c]
In the present study, we got interested in investigating the
conformation
of
Ant-Ant-Pro-Gly
tetrapeptides
and
consequences on exchanging C-terminus ester with amide.
Supporting information for this article is given via a link at the end of
the document. ((Please delete this text if not appropriate))
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10.1002/ejoc.201700181
European Journal of Organic Chemistry
FULL PAPER
Results and Discussion
Solution-state conformational analysis of peptides 5-10:
The strength and the nature of hydrogen bonding interactions
(intermolecular vs intramolecular) in the solution-state can
convincingly be ascertained by solvent titration of the
compounds (dissolved in non-polar solvent) with polar solvents.
DMSO, a polar aprotic solvent, interacts with polar amide NHs
present within the molecule, resulting in change in the chemical
shift values of amide NHs. However, NHs which are involved in
the intramolecular hydrogen bonding are less likely to be
affected by the solvent polarity, and hence show negligible
change in the chemical shift values. Peptides 6, 7, 8 and 9 (5
mM in CDCl3) were titrated gradually against DMSO-d6. Figure 3
(a), (b), (c) and (d) show the change in the chemical shift values
versus the volume (in µL) of DMSO-d6 added for the
tetrapeptides 6, 7, 8 and 9, respectively. The NHs which showed
negligible change in the chemical shift values (≤ 0.41 ppm) were
considered to be involved in intramolecular hydrogen bonding.[11]
It was also evident that the Gly NHs (∆δ NHGly > 0.5 ppm) do not
participate in intramolecular H-bonding in all the peptides.
Further, it became quite clear from the ∆δNHc-terminus values that
the C-terminus NHs of amide analogs 8 and 9, were involved in
Synthesis:
The syntheses of tetrapeptides 5-10 (Figure 2) were carried out
using solution-phase peptide coupling reactions (Supporting
information, page S3 and S10). After extensive attempts with
crystallization trials, we could get the crystals for two peptides (5
and 10). On the other hand, conformational studies of other
selected four peptides (6-9) were undertaken by nOe-based MD
simulated structures.
Figure 2. The general molecular structure (left) of tetrapeptides 5-10 and a
table (right) containing their substitution pattern.
the intramolecular H-bonding (∆δNHc-terminus
≤
0.4 ppm).
NH1
NH2
(a)
(b) 11.0
NH1
NH2
NH3
10.5
10.0
9.5
9.0
8.5
8.0
7.5
7.0
6.5
6.0
10.5
10.0
9.5
9.0
8.5
8.0
7.5
7.0
6.5
6.0
0
10
20
30
40
50
0
10
20
30
40
50
Volume of DMSO-d6 added (µL)
Volume of DMSO-d6 added (µL)
(c)
(d)
NH1
NH1
NH2
NH3
NH4
NH2
NH3
11.0
10.5
10.0
9.5
11.0
10.5
10.0
9.5
9.0
8.5
8.0
7.5
7.0
6.5
6.0
9.0
8.5
8.0
7.5
7.0
6.5
6.0
0
10
20
30
40
50
0
10
20
30
40
50
Volume of DMSO-d6 added (µL)
Volume of DMSO-d6 added (µL)
Figure 3. DMSO-d6 titration studies of the peptides 6 (a), 7 (b), 8 (c) and 9 (d) in CDCl3.
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10.1002/ejoc.201700181
European Journal of Organic Chemistry
FULL PAPER
In order to investigate the solution-state conformational studies
of the peptides, we carried out 2D NMR studies and the signal
assignments were carried out by COSY, TOCSY, HSQC, HMBC
Amide analog
like its ester analog
8
[Figure 5 (a)] showed similar nOe interactions,
6, except showing additional long range
inter-residual nOe interactions such as NH2/NH4 and
C24H/C5H due to the close proximity of the folded termini as a
result of 10-membered H-bond between C-terminus amide NH
and NOESY experiments for all the analogs
characteristic strong nOe interactions such as NH1/C8H,
NH1/C15H and NH2/C15H suggested that peptide [Figure 4
5-10. The
5
and CO group of Ant2. 2D NOESY spectrum of
9 also showed
(a)] showed a similar conformation in the solution-state, as seen
in its crystal structure [Figure 6 (a)]. It is noteworthy that the
similar nOe interactions [Figure (b)]. The presence of
5
NH1/NH3 and C22H/C3H nOe interactions between the
aromatic ring (Ant1) and C-terminus methyl group further
supported the folded conformation.
ester analogs
6 and 7 show similar nOe interactions along with
some additional nOe interactions as shown in Figure 4 (b, c).
(a)
(a)
NH2
ppm
NH1
ppm
NH1/C8H
4.4
NH2/C17H (α)
8.3
C8H
C17H(α)
4.6
ppm
8.4
ppm
ppm
10.4
NH1
10.1
10.0
C24H
NH2
NH2
ppm
ppm
7.6
ppm
7.0
7.1
7.8
NH2/C15H
C24H/C5H
NH2/NH4
7.8
7.9
C15H
C5H
C15H
7.7
ppm
NH1/C15H
NH4
8.0
ppm
10.4
ppm
9.7
2.65
2.60
ppm
10.10
10.05
(b)
(b)
NH1
ppm
8.2
C3H
ppm
C15H
C8H
C3H/C22H
2.55
2.60
NH1/C15H
8.4
8.6
C22H
2.65
ppm
NH1/C8H
7.65
7.60
ppm
11.1 11.0 10.9
NH1
C12H
NH1
NH2
ppm
3.6
ppm
ppm
6.7
ppm
4.6
C12H/C20H (δ)
NH2/C17H (α)
NH1/NH3
3.6
3.8
4.7
4.8
C18H(δ)
6.8
6.9
C20H (δ)
NH3
C17H (α)
NH1/C18H (δ)
3.7
ppm
9.35
4.9
ppm
9.45
9.40
ppm
9.45 9.40 9.35
ppm
7.4
10.3
10.2
7.6
7.5
(c)
(c)
C22H
ppm
C18H (δ) C'18H (δ')
C'18H/C10H
C22H/C3H
C22H/C2H
ppm
7.5
8.0
C3H
C2H
7.3
7.4
7.5
C10H
C18H/C10H
ppm
2.8 2.6
ppm
3.6
3.5
NH1
NH1
NH1
NH1
ppm
6.8
ppm
3.6
ppm
3.5
ppm
NH1/C18H
NH1/C15H (α)
4.6
NH1/NH3
C18H (δ)
3.6
C15H (α)
NH3
NH2
C18H (δ)
3.8
ppm
NH1/C18H (δ)
4.8
ppm
7.0
ppm
3.7
ppm
9.65
9.60
9.6
9.6
9.7
9.6
Figure 4. Selected nOe excerpts for C-terminus ester analogs 5 (a), 6 (b) and
7 (c).
Figure 5. Selected nOe excerpts for the amide analogs 8 (a), 9 (b) and 10 (c).
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10.1002/ejoc.201700181
European Journal of Organic Chemistry
FULL PAPER
The folded conformation observed in the solid-state structure of
peptide 10 [Figure 7 (c)] was clearly reflected in its solution-state
structure as well, as evident from characteristic nOes (NH1/NH3,
C22H/C2H and C22H/C3H) [Figure 5 (c)].
Structural studies of C-terminus ester analogs 5-7:
The single crystal X-ray structure analysis of compound 5[14] is
shown below [Figure 6 (a)]. The amide NHs present on both the
Ant rings are involved in strong 6-membered H-bonding (C6)
with the corresponding carbonyl groups of Ant; with the distance
of 1.9 Å (NH of Ant1) and 2.0 Å (NH of Ant2), respectively. The
NH of Gly4 is directing outwards without participating in
intramolecular H-bonding and the ester group at the C-terminus
is found to be fraying away, presumably due to the repulsive
interactions giving rise to an extended open structure. The MD
simulated structure obtained by using 2D NMR studies for
peptide
for peptide
membered H-bond with CO group of Ant1 and Ant2. The C-
terminus ester group is seen to be fraying away as in peptide
affording an open structure. Ester [Figure 6 (c)] with a N-
6
[Figure 6 (b)] showcases similar structural trend seen
5
with both Ant NHs forming intramolecular 6-
5,
7
terminus NO2 group showed only one 6-membered H-bond,
(Ant2), as expected. It is noteworthy that the C-9 turn, usually
found in Ant-Pro amides,[8, 11] was conspicuously absent in all
these C-terminus esters 5-7.
Figure 7. Molecular structures (left) and corresponding crystal (10) and nOe-
based MD simulated structures of 8, 9 (right) of Ant-Ant-Pro-Gly C-terminus
amides.
Structural studies of C-terminus amide analogs 8-10:
The unpredictable H-bonding features in the Ant-Pro peptide
series prompted us to undertake the conformational studies of
their corresponding amide analogs. Unlike the ester analogs
5-7,
C-terminal amide analogs 10 featured different structural
8-
architecture, essentially dictated by the C-terminus Pro-Gly
amide motif. The nOe-based MD simulated 20 minimum energy
structures for peptide
showed completely folded conformation. Folded structure in
amide was observed owing to the presence of concurrent
8 [Figure 7 (a)] and 9 [Figure 7 (b)]
8
display of 6-membered (involving Ant) and a 10-membered H-
bonding pattern (emanating from the Pro-Gly amide motif).
Similar structural feature was observed for amide
9 (N-teminus
NO2 group) with the presence of 6- and 10-membered H-
bonding pattern giving folded conformation as seen in Figure 7
(b). The crystal structure of peptide 10[14] [Figure 7 (c)] showed a
similar folded structure due to the presence of concerted H-
bonding formed in the backbone (6-membered H-bonding
involving Ant and a 10-membered H-bonding pattern involving
Pro-Gly amide motif) with the H-bonding distance of 2.2 Å and
2.3 Å for 6- and 10-membered H-bond, respectively. Notably, C-
9 turn, usually found in Ant-Pro amides, was conspicuously
absent in all these peptides as well.
Figure 6. Molecular structures (left) and corresponding crystal (5) and nOe-
based MD simulated 20 minimum energy structures 6, 7 (right) of Ant-Ant-Pro-
Gly C-terminus esters.
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10.1002/ejoc.201700181
European Journal of Organic Chemistry
FULL PAPER
Conclusions
peptides 6, 7, 8 and 9 were derived from distant constraints from
nOe cross peaks by using macromodel-v10.8 from Schrödinger
software. For more details, see supporting information.
In conclusion, extensive structural studies of Ant-Ant-Pro-Gly
tetrapeptides provided insights into their folding pattern.
Comparison of their conformations suggested that the C-
terminus ester analogs display an open (extended) structure
having only 6-membered H-bonding network in the backbone,
emanating from Ant residues. However, amide analogs namely
Acknowledgements
S.B.B, A.S.K and S.R.S are thankful to CSIR, New Delhi for
research fellowships. GJS thanks CSIR-SSB project: SSB-
000726 for financial support.
8, 9 and 10 displayed fully folded conformation featuring 10-
membered intramolecular H-bonding pa ttern – dictated by the
Pro-Gly motif. Strikingly, the C-9 turn, usually found in Ant-Pro
amides, was conspicuously absent in all these peptides. Our
studies have provided unexpected structural insights into the
folding pattern of Ant-Ant-Pro-Gly tetrapeptides, which will have
a bearing in the development of de novo peptide sequences
featuring Ant; a work which is currently underway.
Keywords: H-bonding • Folding • chain-fraying • β-turn • MD
simulation
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Crystal data of Compound 10:
Single crystals of 10 were obtained by slow evaporation of the
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colorless plate, 0.40 x 0.33 x 0.19 mm3, monoclinic, space group
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[4]
100.7760(10)°, V = 1071.51(9) Å3, Z = 2, T = 100 K, 2θmax
=
56.00°, Dcalc (g cm–3) = 1.373, F(000) = 464,
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(mm-1) = 0.215,
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The synthesis and characterization of all new compounds are
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The syntheses of the peptides 5-10 were carried out by using
solution-phase peptide coupling reactions. The crystal structure
analysis of compound 5 was done on Bruker D8 VENTURE
Kappa Duo PHOTON II CPAD diffractometer. Crystal structure
analysis of compound 10 was carried out using Bruker SMART
APEX II CCD diffractometer. Solution-state 2D NMR studies
were carried out in CDCl3 on AV 500 MHz Bruker NMR
spectrometer. Molecular dynamics NMR-based structures of
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10.1002/ejoc.201700181
European Journal of Organic Chemistry
FULL PAPER
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10.1002/ejoc.201700181
European Journal of Organic Chemistry
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Key Topic*
Sachin B. Baravkar, Amol S. Kotmale,
Samir R. Shaikh, Rajesh G. Gonnade
and Gangadhar J. Sanjayan *
Page No. – Page No.
Structural Insights into the Hydrogen-
Bonding and Folding Pattern in Ant-
Ant-Pro-Gly Tetrapeptides
Synthesis and conformational analysis of peptides containing C-terminal ester and amide was undertaken. Conformational
analysis was carried out by using 2D NMR spectroscopy and X-ray crystallographic studies which proved that ester analogs
displayed an extended conformation, whereas, amide analogs demonstrated folded conformation owing to the presence of C-
terminus β-turn.
This article is protected by copyright. All rights reserved.