Can Side Chain Interactions Nucleate Supramolecular Heterogeneity

Article pubs.acs.org/crystal

Can Side Chain Interactions Nucleate Supramolecular Heterogeneity in Synthetic Tripeptides? Ankita Sharma Gangele,† Soumyabrata Goswami,‡ Arun Kumar Bar,‡ Priyanka Tiwari,† Sanjit Konar,*,‡ and Anita Dutt Konar*,† †

School of Pharmaceutical Sciences and Department of Chemistry, Rajiv Gandhi Proudyogiki Vishwavidyalaya, Airport By-pass Road, Gandhinagar, Bhopal 462033, Madhya Pradesh, India ‡ Department of Chemistry, IISER Bhopal, Bhopal By-pass Road, Bhauri, Bhopal 462066, Madhya Pradesh, India S Supporting Information *

ABSTRACT: In an attempt to artificially imitate the importance of side chains in supramolecular architecture stabilization, we have synthesized a set of four model tripeptides Boc-4(X)-Phe-Aib-Yaa-OMe (I−IV), where X = I, F, N3, and Yaa = Ile/Leu, respectively. Our experimental (X-ray crystallography) and computational investigation (differential functional theory calculations) reveals that the tripeptide (I) self-assembles to form a zigzag ribbon-like assemblage between two conformers, a type III β-turn and an open strand, present in the asymmetric unit. In contrast when a slight modification has been incorporated in the side chains in tripeptides II−IV, it does not support the formation of a ribbon-like organization. Instead, significant heterogeneity is displayed within the supramolecular framework. Interestingly, field emission scanning electron microscopy studies also support the morphological diversities present in the peptides arising due to a mere change of terminal side chains. Thus, the importance of co-operative steric interactions among the side chains of amino acid residues is emphasized in stabilizing a particular supramolecular architecture. This research may not only serve to indicate effective candidates in protein modification but also assist in the rational design of peptidomimetics.

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INTRODUCTION Previous studies on protein folding have mainly focused on the backbone conformational preferences.1−14 However, in peptides and proteins, not only the backbones but also the side chain/side chain interactions play a vital role in stabilizing supramolecular architectures.15−22 Supramolecular assemblies are ubiquitous in nature from the perspective of fundamental science.23−36 Over the past few years, several approaches have been devised to stabilize these assemblies using a combination of weak interactions such as hydrogen bonding, electrostatic interactions, π−π interactions, halogen bonding, etc.37−55 However, the reported assemblies are mainly stabilized by backbone interactions of building blocks.56−72 Thus, the design of synthons involving tunable side chain functionalities remains in a rudimentary stage.73−76 As a part of the investigation, herein we present the diversities in self-assembly propensities of a set of four different synthetic tripeptides Boc-4(X)-Phe-Aib-Yaa-OMe (I−IV) differing in terminal side chains. When the N-terminal position is occupied by Boc-4(I)-Phe, Aib (Aib: α-amino isobutyricacid) at the central position and a bulky hydrophobic residue, Ile, at the C-terminus (peptide I) display supramolecular preference for a zigzag ribbon-like organization (Figure 1). Keeping in mind the role displayed by iodine in thyroid hormone,77−80 we decided to introduce the simple iodinated derivative of phenylalanine, i.e., (4-(I) Phe), in the sequence © 2016 American Chemical Society

Figure 1. Chemical structures of peptides I−IV.

and explore its implications in the self-assembly process. As a further design element, Aib was chosen to introduce crystallinity and helicity, followed by Ile to promote considerable hydrophobicity within the sequence. In contrast, the isomeric tripeptide Boc−4(I)−Phe−Aib−Leu−OMe (II), where the third residue of peptide I has been interchanged by leucine, does not support the formation of a zigzag ribbon-like architecture. Moreover, our systematic studies further reflect Received: December 21, 2015 Revised: February 1, 2016 Published: February 11, 2016 2130

DOI: 10.1021/acs.cgd.5b01803 Cryst. Growth Des. 2016, 16, 2130−2139

Crystal Growth & Design

Article

trifluoroacetic acid was removed under reduced pressure to afford the crude trifluoroacetate salt. The residue was taken in water and washed with diethyl ether. The pH of the aqueous solution was adjusted to 8 with sodium bicarbonate and extracted with ethyl acetate. The extracts were pooled, washed with saturated brine, dried over sodium sulfate, and concentrated to a highly viscous liquid that gave a positive ninhydrin test. This tripeptide free base was added to an ice-cold solution of Boc-4(I)-Phe-OH (400 mg, 1.02 mmol) in DMF (4 mL) followed by TBTU (394 mg, 1.22 mmol). The reaction mixture was stirred at room temperature for 4 days. The residue was taken in ethyl acetate. The organic layer was washed with 2 M HCl (3 × 50 mL), 1 M Na2CO3 solution (3 × 50 mL) and brine, dried over anhydrous Na2SO4, and evaporated in vacuo, to yield a white solid. Purification was done using silica gel as the stationary phase and an ethyl acetatepetroleum ether mixture as the eluent. Single crystals were grown from an acetone-petroleum ether mixture by slow evaporation and were stable at room temperature. Yield: 0.62 g (0.92 mmol, 90%). Mp = 96−94 °C; HR-LC-MS: 604.1849 [M + H]+; MS (calculated) m/z: 603 [M]+, IR: 3442, 3340, 3301, 1744, 1691, 1652, 1525 cm−1; 589[α]25 = −201° (c = 2 mg per 3 mL; CH3OH); 1H NMR 400 MHz (CDCl3, δ ppm): 7.14 (phenyl ring protons of 4(I)−Phe(1), 4H, m); 6.96 (Ile(3) NH, 1H, d, J = 8 Hz), 6.22 (Aib (2) NH, 1H, s), 5.01 (4(I) Phe(1), NH,1H, br), 4.56− 4.52 (CαH of Ile (3),1H, m), 4.15−4.13 (CαH of 4(I) Phe(1), 1H, m), 3.69 (−OCH3, 3H, s), 3.02−3.00 (CβHs of 4(I)−Phe(1), 2H, d, J = 8 Hz), 1.66−1.54 (CβH and CγH s of 4(I)Phe(1), 6H, m), 1.44 (CβHs of Aib (2), 6H, s), 1.40 (Boc−CH3s, 9H, s), 0.92−0.90 (CδHs of Ile(3), 3H, m), 13C NMR 400 MHz (CDCl3, δ ppm): 173.8, 172.5, 170.4, 137.7, 136.3, 131.4, 98.1, 92.2, 80.4, 57.4, 56.8, 52.1, 37.8, 28.2, 25.5, 24.7, 15.5, 11.6. Peptide II. Peptide II was synthesized following a similar procedure as described for I starting from Boc-Aib-Leu-OMe and Boc-4(I)-PheOH. Single crystals were grown from an acetone-petroleum ether mixture by slow evaporation and were stable at room temperature. Yield: 431 mg (70%, 0.72 mmol). Mp = 161−159 °C; HR-LC-MS: 604.1849 [M + H]+; MS (calculated) m/z: 603 [M]+; IR: 3385, 3365, 3308, 1736, 1688, 1654, 1544 cm−1; 589[α]25 = −26.6° (c = 7 mg per 3 mL; CH 3OH); 1H NMR 400 MHz (CDCl3, δ ppm): 7.62−7.60 (phenyl ring protons of 4(I)-Phe(1), 2H, d, J = 8 Hz), 6.97−6.95 (phenyl ring protons of 4(I)−Phe, 2H, d, J = 8 Hz), 6.91 (Leu (3) NH, 1H, d, J = 8 Hz), 6.45 (Aib(2) NH, 1H, s), 4.96 (4(I) Phe(1), NH, 1H, br), 4.52−4.49 (CαH of Leu (3), 1H, m), 4.21−4.20 (CαH of 4(I) Phe(1), 1H, m), 3.70 (−OCH3, 3H, s), 3.06−2.97 (CβHs of 4(I)−Phe(1), 2H, m), 1.87 (CβHs of Leu(3), 2H, m), 1.49 (CβHs of Aib(2), 3H, s), 1.44 (CβHs of Aib(2), 3H, s), 1.40 (Boc−CH3s, 9H, s), 1.17−1.12 (CγHs of Leu(3), 1H, m), 0.92−0.88 (CδHs of Leu(3), 3H, m); 13C NMR 400 MHz (CDCl3, δ ppm): 173.8, 173.5, 170.3, 137.8, 137.4, 136.5, 131.4, 92.5, 80.6, 57.3, 52.2, 51.0, 41.2, 28.3, 28.2, 25.7, 24.8, 24.5, 22.9, 21.8. Peptide IV. Peptide IV was synthesized following a similar procedure as described above starting from Boc−Aib−Leu−OMe and Boc−4(N3)−Phe−OH. Single crystals were grown from an acetone-petroleum ether mixture by slow evaporation and were stable at room temperature. Yield: 700 mg (80%,1.06 mmol). Mp = 150−152 °C; HR-LC-MS: 514.6100 [M − 4H]+; MS (calculated) m/z: 518 [M]+; IR: 3384, 3361, 3303, 1735, 1693, 1652, 1506 cm−1; 589[α]25 = −98.0° (c = 1 mg per 3 mL; CH3OH); 1H NMR 400 MHz (CDCl3, δ ppm): 7.19−7.16 (phenyl ring protons of 4(N3)−Phe, 2H, m), 6.96−6.93(phenyl ring protons of 4(N3)−Phe, 2H, d, J = 8 Hz), 6.93−6.91 (Leu(3) NH, 1H, d, J = 8 Hz), 6.46 (Aib(2) NH, 1H, s), 5.03 (4(N3) Phe(1), NH, 1H, br), 4.52−4.49 (CαH of Leu (3), 1H, m), 4.20−4.19 (CαH of 4(N3)− Phe(1), 1H, m), 3.71 (−OCH3, 3H, s), 3.03−3.00 (CβHs of 4(N3)− Phe(1), 2H, br), 1.92−1.83 (CβHs of Leu(3), 1H, m), 1.48 (CβHs of Aib(2), 3H, s), 1.43 (CβHs of Aib(2), 3H, s), 1.39 (Boc-CH3s, 9H, s), 1.26−1. 10 (CγH of Leu(3), 1H, m), 0.92−0. 87 (CδHs of Leu(3), 6H, m); 13C NMR 400 MHz (CDCl3, δ ppm): 174.1, 173.4, 138.9, 133.4, 132.7, 130.9, 119.4, 119.2, 80.8, 57.1, 52.1, 50.9, 41.3, 28.5, 25.9, 25.6, 24.8, 24.6, 22.9, 21.8.

that changing the positions of 4-(I)-Phe, by 4-(F)-Phe- in peptide III13 and 4-(N3)-Phe in peptide IV does not stabilize this ensemble. Instead a supramolecular sheetlike structure (peptides II and III) and a helix (peptide IV) is formed employing hydrogen bonding and noncovalent interactions as the driving force. We have tried to explain this supramolecular heterogeneity using density functional theory with the help of the Gaussian 09 program.81 Our computational investigation supports our experimental observation and emphasizes that an optimum balance of side chain interactions between the two terminal residues of tripeptides is unprecedented. This balance of weak interactions, resulting in significant enthalpic stabilization, immensely influences the fashion of selforganization in tripeptides. Moreover, this supramolecular diversity is also evident from the scanning electron microscopy studies.

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EXPERIMENTAL SECTION

Synthesis of Peptides. Peptides I−II and IV containing a Boc group at the N-terminus and methoxy carbonyls at the C-terminus were synthesized using conventional solution phase methodology, with racemization-free techniques. The process was followed by a fragment condensation strategy, employing dicyclohexylcarbodiimide (DCC)/1hydroxybenzotriazole HOBT) and TBTU as coupling agents.82 Methyl ester hydrochlorides of Ile/Leu were prepared by the thionyl chloride-methanol procedure. All the intermediates obtained were checked for purity by thin layer chromatography (TLC) on silica gel and used without further purification. All the final peptides were purified by column chromatography using silica gel (100−200 mesh) as the stationary phase and an ethyl acetate and petroleum ether mixture as the eluent. The reported peptides I−II and IV were fully characterized by X-ray crystallography, NMR, and IR spectroscopy. Peptide I. To Boc-Aib-Ile-OMe, (562 mg, 1.70 mmol) trifluoroacetic acid (3 mL) was added at 0 °C and stirred at room temperature. The removal of the Boc- group was monitored by TLC. After 12 h the

Table 1. X-ray Crystallographic Data and Refinement Parameters for peptides I, II, and IV I

II

formula MW (g mol−1) cryst syst space group T (K) a (A) b (A) c (A) β (deg) V (Å3) Z ρcalcd (g cm−3) μ (Mo Kα) (mm−1) R1, wR2 (all data)a

C25H35IN3O6 602.73 monoclinic P21 110 10.9427(9) 21.2628(18) 24.561(2) 97.287(2) 5668.5(8) 8 1.413 1.171 0.0517, 0.0962

C25H38IN3O6 603.48 monoclinic P21 110 14.0875(13) 29.062(3) 14.2371(13) 103.719(2) 5662.5(9) 8 1.416 1.172 0.0816, 0.2088

R1, wR2 (I > 2σI)a

0.0443, 0.0924

0.0781, 0.2063

collected reflections unique reflections goodness-of-fit (GOF) on F2 Flack parameter R(int) CCDC No.

20127 16916 1.042

23165 12653 1.048

C25H38N6O6 518.61 monoclinic P21 110 8.8283(5) 11.1669(7) 14.5607(9) 91.043(3) 1435.23(15) 2 1.200 0.087 0.1146, 0.1640 0.0568, 0.1332 7296 3958 0.953

0.001(5) 0.0316 1059542

0.002(3) 0.0231 1059543

1(3) 0.0289 1059545

a

IV

R1 = Σ∥Fo| − |Fc∥/Σ|Fo|. wR2 = |Σw(|Fo|2 − |Fc|2)|/Σ|w(Fo)2|1/2. 2131



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−54.8(6); ψ2: −37.4(7), −38.9(6) (Table 2), which are slightly deviated from the ideal values for a type III β-turn ϕ1: −60, ψ1:

NMR Experiments. All 1H NMR studies were recorded on a Bruker Avance 500 model spectrometer operating at 400 MHz, respectively. The peptide concentrations were in the range 5−10 mM in CDCl3 for 1 H NMR spectroscopy. X-ray Single Crystal Data Collection and Structure Determination. Single crystal X-ray data collection of peptides I−II and IV were performed at 110 K on a Brüker Smart Apex−II CCD diffractometer with graphite monochromated Mo−Kα (λ = 0.71073 Å) radiation. Data collections were performed using φ and ω scans. The structures were solved using direct methods followed by full matrix least-squares refinements against F2 (all data HKLF 4 format) using SHELXTL.43−83 A “Multi-Scan” absorption correction, based on equivalent reflections, was applied to the data. Anisotropic refinement was used for all non-hydrogen atoms. Hydrogen atoms were placed in appropriate calculated positions. In peptides I, II, and IV the presence of “Low Bond Precision on C−C Bonds” (Check cif) can be attributed to a weakly diffracting crystal which results in a poor data to parameter ratio. Particularly, for peptides I and II geometric and thermal displacement parameter restraints like EADP and DELU were used to keep the refinement stable. However, for peptide IV, although crystal quality was poor, no constraints were required. X-ray crystallographic data of peptides I, II, and IV in CIF format are available for CCDC numbers 1059542, 1059543, and 1059545 respectively. Differential Functional Theory (DFT) Computations. The input files were set using crystallographic coordinates of the peptide molecules. In order to simplify the systems for convenient DFT calculations, only the repeat unit of the extended network of the corresponding peptide was excerpted. B3LYP basis function85,86 and LANL2DZ (for I) and 6-31+G(d,p) (for the rest of the elements) basis sets87 were employed for the computations. Single point energy and electronic excitation states were calculated employing TD−DFT with the above-mentioned basis function and basis sets allowing d and p as well as HOMO and LUMO orbital mixing. Field Emission Scanning Electron Microscopic Study. Morphology of peptide I, II, and IV were investigated using FE-SEM microscope (JEOL JSM-6700F). For the study, fibrous materials (slowly grown from acetone and petroleum ether, the same solvent as that used in crystallization) were dried and gold coated.

Table 2. Selected Backbone Torsion Angles (°) of Peptides I, II, and IV torsion angles Peptide I ω0a ϕ1 ψ1 ω1b ϕ2 ψ2 ω2c ϕ3 ψ3 Peptide II ω0a ϕ1 ψ1 ω1b ϕ2 ψ2 ω2c ϕ3 ψ3 Peptide IV (ω0)a (ϕ1) (ψ1) (ω2)c (ψ3)

Mol A

Mol B

Mol C

Mol D

177.3(5) −59.3(7) −21.2(7) 179.6(5) −52.1(6) −37.4(7) −179.2(5) −128.6(6) −57.5(7)

167.1(4) −58.8(6) −22.3(6) 179.0(4) −54.8(6) −38.9(6) −179.1(4) −126.9(5) −92.0(5)

−172.2(4) −67.2(6) −32.8(7) 172.3(5) 51.8(6) 51.3(6) 177.1(5) −99.2(6) 125.0(5)

−171.7(4) −66.9(6) −32.1(7) 168.4(5) 52.8(7) 45.5(7) 177.3(5) −82.2(6) 133.6(5)

176(1) −62(1) 128(1) 177(1) 64(1) 24(1) −179(1) −132(1) −163(1)

178.6(9) −65(1) 125(1) 178(1) 59(1) 29(1) 175(1) −119(1) 177(1)

177.5(9) −61(1) 129(1) 175(1) 62(1) 26(1) −177(1) −136(1) −165(1)

176.4(9) −62(1) 126(1) 175(1) 63(1) 26(1) 178(1) −120(1) 175(1)

−177.6(3) −60.8(4) 126.1(3) −178.0(3) −173.5(3)

(ω1)b (ϕ2) (ψ2) (ϕ3)

175.2(3) 60.5(4) 27.6(4) −133.1(4)

a Torsion angle around the amide C−N bond at the N-terminal of the peptides. bTorsion angle around the peptide C−N bond between 4(I)-Phe(1) and Aib(2) of the peptides I and II and 4-(N3)-Phe(1) and Aib(2) of peptide IV. cTorsion angle around the peptide C−N bond between Aib(2) and Ile(3)/Leu(3) of the peptides I, II, and IV respectively.

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RESULTS AND DISCUSSION Solid State Structure. The solid state structure reveals that in the asymmetric unit peptide I crystallizes in two different conformations, a turn and an open strand form (A and B in turn conformation and C and D in open strand conformation). Careful examination of the crystal structures of the turns (A and B) reveal a type III β-turn with 4-(I)-Phe(1) and Aib(2) occupying the i+1 and i+2 positions respectively, stabilized by an intramolecular hydrogen bond (Figure 2). The torsion angles at 4-(I)-Phe(1) and Aib(2) are found to be ϕ1: −59.3(7), −58.8(6); ψ1: −21.2(7), −22.3(6) and ϕ2: −52.1(6),

−30 and ϕ2: −60, ψ2: −30.88 As a result a weak intramolecular hydrogen bond between Boc-CO and Ile(3)-NH is observed (Table 3). From the torsion angles of the other two conformers (C and D) (ϕ1: −67.2(6), −66.9(6), ψ1: −32.8(7), −32.1(7) and ϕ2: 51.8(6), 52.8(7); ψ2: 51.3(6), 45.5(7)) it is evident that the molecule adopts an open structure with three “kinks” along the peptide backbone (Table 2). It is interesting to note that the torsion angles around the Cα of Aib are in the right-handed α-helical region (ϕ2: −52.1(6), −54.8(6); ψ2: −37.4(7), −38.9(6) for the turns, and in the left-handed α-helical region for the open strand conformation (ϕ2: 51.8(6), 52.8(7); ψ2: 51.3(6), 45.5(7)) (Table 2). This variation in torsion angles around the centrally positioned Aib appear to play a crucial role in dictating the conformational diversities within the peptide backbone (Figure 2, Table 2; Figures S1−S5, SI). Each type III β-turn and open strand molecules of peptide I are regularly interlinked via intermolecular hydrogen bonds to form two different strands of a zigzag ribbon along the b-axis. There are four different types of hydrogen bonds that stabilize the assembly. They are (a) (4(I)Phe(1)-NH of (Mol A turn/ Mol B turn) with 4(I)Phe (1)-CO of (Mol C open strand/Mol D open strand); (b) Ile(3)NH of (Mol C strand/Mol D strand) with Ile(3) CO group of (Mol A turn/Mol B turn);

Figure 2. Crystal structure of peptide I showing two different conformations: (a) turn (Mol A); (b) open strand (Mol C) in the asymmetric unit. Hydrogen bonds are shown as dotted lines. 2132



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Table 3. Hydrogen Bonding Parameters of Peptide I D−H−−A Intramolecular N6H6-----O7 Intermolecular N4H4-----O15ia N5H5-----O16ia Molecule B (turn) Intramolecular N3H3-----O1 Intermolecular N1H1-----O21b N2H2-----O22b C26 I2----------O4c Molecule C (open structure) Intermolecular N7H7-----O10id N9H9-----O11id Molecule D (open structure) Intermolecular N10H10-----O4ie N12H12-----O5e

H−A/I−−O (Ǻ )

X−−O (Ǻ )

D−H−−A/X−I−−O (°)

2.37

3.11

144.44

2.16 2.29

2.99 2.84

161.49 121.68

2.40

3.20

154.14

2.08 2.36 3.04

2.92 2.95 5.15

165.96 126.20 176.76

2.24 2.19

3.05 3.02

157.44 163.66

2.14 2.23

2.95 3.02

156.82 153.01

Figure 3. (a) Ball and stick and (b) space filling model of peptide I showing a zigzag ribbon-like architecture using both turn and open strand conformation along the b-axis.

x, y, z. bx, y, 1 + z. c1 + x, y, z. d−x, 1/2 + y, 1 − z. e−x, −1/2 + y, 1 − z. a

(c) Aib(2) NH of (Mol A turn/Mol B turn) with Aib(2) CO of (Mol C strand/Mol D strand); (d) 4(I)Phe(1)-NH of (Mol C strand/Mol D strand) with Aib(2) CO group of (Mol A turn/Mol B turn) (Table 3). The first strand of the ribbon is formed by the first two hydrogen bonding interactions (a and b) and the second strand by (c and d). Moreover it has been found that the Aib(2) CO of Mol B is interconnected to the iodine molecule of 4(I)Phe(1) of Mol A to form a bifurcated iodine mediated halogen bond, resulting in the stabilization of a one-dimensional supramolecular sheet as viewed along the crystallographic a/b-axis (Figure 4). The word bifurcated has been used as the Aib(2) CO acts as an acceptor for a hydrogen bond and a halogen bond (4(I)Phe(1) NH of Mol C and iodine of 4(I)Phe (1) of Mol B) (Table 3). Figure 5 depicts a view of the iodine mediated supramolecular sheet as observed along the crystallographic a/b-axis. Previously, several groups have reported supramolecular sheet formation through proper alignment of semicylindrical structure using hydrogen bonding and various noncovalent interactions.5,6,13,14 However, our work significantly differs from the earlier reports because for the first time they represent monolayer sheet formation through iodine mediated halogen bonding as viewed along the crystallographic a/b-axis. This sheetlike ensemble is formed by proper alignment of a zigzag ribbon-like assembly of peptide I that exists in two different conformations in the asymmetric unit. In order to gain insight regarding the importance of a third residue in the nucleation of a zigzag ribbon-like organization, the Ile of peptide I was replaced by isomeric Leu in peptide II. Interestingly, peptide II which also crystallizes with four molecules in the unit cell (Mol A−Mol D), exhibits no such diversities within the peptide backbone. Instead a similar type of type II β-turn conformation is observed for all the molecules (Table 2, Figure 6a; Figures S6−S10, SI).

Figure 4. Sheetlike structure formed through iodine mediated halogen bonding of peptide I along the crystallographic a/b axis.

Figure 5. Sheetlike structure formed through iodine mediated halogen bonding of peptide I as viewed done along the crystallographic a/b axis.

Each type II β-turn molecules of peptide II are regularly interlinked via intermolecular hydrogen bonds between the 4(I)Phe (1)-NH of Mol A/MolC and the Leu(3)−CO group of Mol B/Mol D to create a semi-cylindrical structure parallel to the crystallographic b-axis (Table 4). It is further observed that the Aib(2)−NH of Mol A/MolC is hydrogen 2133



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Figure 6. Crystal structures of peptide II and IV with atom numbering scheme. Intramolecular hydrogen bonds are shown as dotted lines.

Table 4. Hydrogen Bonding Parameters of Peptide II D−H−−−A Molecule A (turn) Intramolecular N8H8A-----O16a Intermolecular N9H9-----O10ib N7H7-----O4a Molecule B (turn) Intramolecular N6H6-----O00Aa Intermolecular N12H12-----O15c N5H5-----O18ib Molecule C (turn) Intramolecular N3H3-----O1a Intermolecular N2H2-----O9a Molecule D (turn) Intramolecular N10H10-----O21a Intermolecular N13H13-----O13d a

H−−−A (Ǻ )

D−−−A (Ǻ )

D−H−−−A (°)

Figure 7. Wireframe model of peptide II showing a supramolecular sheet structure as viewed down along the crystallographic a/b axis. 2.31

3.09

148.93

2.08 2.08

2.92 2.96

165.96 174.72

Table 5. Hydrogen Bonding Parameters of Peptide IV

2.31

3.12

153.59

2.19 2.05

3.05 2.93

164.71 172.29

2.41

3.21

150.98

2.08

2.96

173.08

2.34

3.01

144.89

2.09

2.97

173.81

D−H−−−A Intramolecular N3H3A-----O2 Intermolecular N2H2A-----O4a a

H−−−−A (Ǻ )

D−−−−A (Ǻ )

D−H−−−−A (°)

2.41

3.17

147.11

2.17

3.02

170.95

−1 + x, y, z.

x, y, z. b−1 + x, y, z. cx, y, 1 + z. dx, y, −1 + z.

bonded to an Aib (2)CO group of a neighboring turn Mol B/Mol D to produce a corrugated sheet-like structure along the crystallographic a/b-axis (Figure 7; Figures S13−S14, SI). One of our earlier report suggests that replacement of iodine in peptide I by fluorine in peptide III does not stabilize the zigzag ribbon-like architecture. Instead a supramolecular sheetlike structure is formed, stabilized by hydrogen bonding and noncovalent interactions.13 In order to further exemplify the importance of 4(I)Phe and Ile in a zigzag ribbon-like organization, herein our effort is to replace the iodine in phenylalanine by a highly electron withdrawing azido group and Ile by isomeric Leu. Interestingly, peptide IV which adopts a type II conformation as a subunit also fails to form a ribbon-like architecture in higher order selfassembly. Instead, a supramolecular single helical structure is formed (Table 2, Table 5, Figure 8). The principle guidelines of self-assembly involves a balance between enthalpy and entropy, the nature of weak interactions,

Figure 8. Peptide IV self-assembles to form supramolecular helical architecture along the a-axis.

such as hydrogen bonds and noncovalent forces involved, resulting in thermodynamic minimum conditions. A thorough literature survey reveals that the tripeptides containing Phe-Aib in the corner position, irrespective of the third residue, or substitution of NH by NMe, displays conformational preference for β-turns, that adopts a supramolecular sheetlike structure on self-assembly (entry 1−5, Table 6). Similarly, in tripeptides, when the 4(OH)−Phe−Aib occupies the corner residue it forms double helical architecture on self-assembly (entry 6−8, Table 6). From these results (Table 6), it is evident that in tripeptides when a fragment of aromatic chiral amino acid (1) is followed by an achiral amino acid (2), irrespective of the third residue, nucleates a conformation, that functions as subunits for formation of a particular supramolecular assembly. However, this theory does not hold in the case of (X)−Phe− 2134



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Table 6. List of Tripeptides with Phe and Derivatives of Phe and Aib as Corner Residues (Entry 1−11) with Torsion Angles (◦) of the Residues, Subunits, and Supramolecular Assembly Resulting Therefrom entry

peptides

ϕ1 (°)

ψ1 (°)

ϕ (°)

ψ2 (°)

subunit

supramolecular assembly

1. 2. 3. 4. 5. 6. 7. 8. 9.

Boc-4(H)-Phe -Aib-Ile-OMe Boc-4(H)-Phe -Aib-Leu-OMe Boc-4(H)-Phe-Aib- mABA-OMe Boc-NMe- Phe-Aib-Phe-OMe Boc-NMe- Phe-Aib-mABA-OMe Boc-4(OH)-Phe -Aib-Ile-OMe Boc-4(OH)-Phe -Aib-Ala-OMe Boc-4(OH)-Phe-Aib-Leu-OMe Boc-4(F)-Phe-Aib-Ile-OMe Mol. A Mol. B Boc-3(F)-Phe-Aib-Leu-OMe Boc-2(F)-Phe-Aib-Leu-OMe Boc-4(I)-Phe-Aib-Ile-OMe Mol. A Mol. B Mol. C Mol. D Boc-4(I)-Phe-Aib-Leu-OMe Mol. A Mol. B Mol. C Mol. D Boc-4(N3)-Phe-Aib-Leu-OMe

−59.2 −62.0 −61.6 −54.9 55.6 52.1 −59.0 −50.7 64.0 72.7 −64.1 63.5 −59.3 −58.8 −67.2 −66.9 −62.0 −65.0 −61.0 −62.0 −61.1

154.2 127.5 142.0 −41.6 31.5 −125.7 134.7 119.1 −130.4 −119.7 126.0 −129.1 −21.2 −22.3 −32.8 −32.1 128.0 125.0 129.0 126.0 126.2

62.5 61.5 63.6 −59.4 54.3 −64.2 67.3 62.4 −66.3 −19.0 −63.2 −59.8 −52.1 −54.8 51.8 52.8 64.0 59.0 62.0 63.0 60.6

30.9 26.6 22.6 −26.2 33.9 −21.8 21.6 26.4 −61.0 −22.0 24.0 −27.7 −37.4 −38.9 51.3 45.5 24.0 29.0 26.0 26.0 27.3

Type II Type II Type II Type III Type III′ Type II′ Type II Type II Type II′ Type II′ Type II Type II′ Type III Type III Open struc open struc Type II Type II Type II Type II Type II

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2 3 4 72 72 69 69 69 13

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10. 11. 12.

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single crystal X-ray structures and are used for single point energy calculations. However, single crystal X-ray diffraction analyses reveal two conformational isomers (open structure and type-III β-turn; Figure 3) for peptide I and one type of conformational isomer (β-type turns) for the rest of the peptides in their solid state. On the other hand, geometry optimization studies yielded βtype turns as the stablest conformers (Figure 9) in the gas

Aib (X = F, I) containing tripeptides that exhibit anamolous behavior in the solid state (Table 6, entry 9−13). Careful inspection of the structure reveals that peptide I, when the third residue is Ile, exhibits variation in torsion angles around the centrally positioned Aib residue, among the different molecules present in the asymmetric unit. This results in the simultaneous existence of two different conformers that nucleates zigzag ribbon like ensemble upon self-assembly (Table 6, entry 12). However, when Ile of peptide I is replaced by isomeric Leu in peptide II (Table 6, entry 13), it fails to exhibit this variation in torsion angles around Aib. This diversity may be attributed to the influence of favorable interactions among 4(I)-Phe and Ile side chains, resulting in an optimum balance between enthalpic and entropic condition, summing up to the thermodynamically minimum condition. In the case of peptide II−IV (Table 6, entry 12, 9, 14) this interaction among the other residues may not be optimum for stabilizing the zigzag ribbon-like structure. Our computational investigation may provide further insight into the importance of co-operative steric interactions among the side chains of amino acid residues in stabilizing supramolecular architectures. Computational Investigation. Distinctly different supramolecular self-organizations in the solid state of the peptides upon substitution with different side chains inspired us to investigate enthalpic stabilizations resulting from such selfassociations. In this regard, detailed gas−phase optimization and single-point energy calculations have been performed using density functional theory (DFT) with the help of the Gaussian09 proggramme.81 The B3LYP level of theory85,86 was used for geometry optimization and single point energy calculations for all the peptides. The LANL2DZ basis set87 was employed for iodine, and the 6-31G* basis set was introduced for the rest of the elements. d and p as well as HOMO and LUMO orbital mixing was allowed in the single point energy calculation. The coordinates of all the conformers (Figure S15, SI) and the repeat units (Figure S16, SI) of the extended ensembles of the peptides in their solid state are generated from

Figure 9. Capped-sticks model of energy optimized geometries of the peptides I−IV. H atoms are omitted for clarity. Color codes: gray = C; blue = N; red = O; green = F and violet = I.

phase for all the peptides. Interestingly, the gas-phase energy optimized geometries are found to be considerably stabler than the corresponding β-type turns as determined crystallographically for all the peptides (Table S1, SI). The repeat unit of the 3D arrangement of peptide I in the solid state comprises of a pair of each of type-III β-turns (Mol A and Mol B) and open structures (Mol C and Mol D, Figure S15). Surprisingly, the main contribution (−1.57 eV per repeat unit,Figure S17; see SI) to the overall enthalpic stabilization (−1.77 eV per repeat unit) for this 3D arrangement of peptide 2135



Article

iodide in peptide II results in significantly weaker packing stabilization (−0.27 eV per H-bonding for IV vs −0.46 eV per H-bonding for II) for the former. Thus, our theoretical studies are in good agreement with our experimental observation. Morphological Studies. In order to examine whether this supramolecular heterogeneity in the tripeptides is also evident within the morphology, we have tried to grow some materials from the same solvent as that of crystallization. The field emission scanning electron microscopy (FE-SEM) images of the dried fibrous material of peptide I, II, and IV are presented in Figure 10. Interestingly the FESEM images of peptide I (Figure 10a) show a twisted tapelike morphology which may be formed through self-association of ribbon-like entities in higher order self-assembly. The supramolecular ribbon-like assembly of peptide I generated from primary building blocks, type III βturn and open structure (Figure 3) aggregate through intermolecular H-bonds between the peptide linkages of adjacent molecules to generate this morphology in hierarchical organization. Interestingly, the FE-SEM images of peptide II (Figure 10b) and IV (Figure 10c) display twisted ribbons and nontwisted filaments and ribbons respectively, under similar conditions. Thus, our scanning electron microscopy images reflect the morphological diversity displayed by the tripeptides arising due to the mere change of terminal side chains. The observation of various morphological ensembles resulting due to the variation in hydrophobicity (such as a variation in length of the peptide chain, the contribution of side chains and several other factors) has been observed earlier.13,14,89 Various attempts to fabricate these types of structures using amyloid proteins, peptides, and viruses have been reported.90−96 These morphological assemblies may find useful applications in nanoscience and nanotechnology.

I arises from the zigzag ribbon-like association (Figure 3). Notably, in this 3D arrangement of peptide I, the halogen (iodine) bonding interactions are involved only in the formation of a sheet-like structure (Figure 5), which has relatively less impact (−0.1 eV per halogen bonding, Figure S18; SI) on the overall enthalpic stabilization. But, in the case of peptide II, only one type of conformer (type-II β-turn, Figure 6) replicates in the solid state via intermolecular Hbonding interactions to form a grid-like 2D sheet (Figure 7) where 50% moieties are involved in H-bonding interactions with two neighboring molecules and the rest of the moieties associate H-bonding interactions with four neighboring molecules. However, a composite of eight molecules of peptide II is considered as the repeat unit of the 2D sheet, which consists of seven H-bonding interactions (Figure S16). Computational details revealed that such a 2D arrangement of peptide II is stabilized considerably (−0.46 eV per Hbonding). It is noteworthy that peptide III, where the halide is fluorine in place of the iodine of peptide I, does not exhibit ribbon-like organization in the solid state.86 Instead, only one type of conformer (type-II′ β-turns, Figure S19) self-associate via supramolecular interactions to form a 3D arrangement in the solid state (Figure S19, see SI), which is poorly stabilized (−0.35 eV per repeat unit, Figure S16). Furthermore, peptide IV exhibits merely a helical 1D chain comprising only one type of conformational isomer (type-II β-turn, Figure 8) in the solid state and such a 1D arrangement is also found to be weakly stabilized (−0.54 eV per repeat unit, Figure S16). It can be concluded that the substituents on the phenyl group of phenylalanine as well as the alkyl side chains of the terminal amino acids have immense influence on the fashion of self-organization of the tripeptides in their solid state. It is quite obvious that multicomponent self-association into an extended ribbon rearrangement driven by supramolecular interactions renders a huge entropy loss. Such a process is feasible only if the enthalpy gain can overcome the entropy loss, which is mainly monitored by the presence of functional groups, steric hindrance, and thermal motions of the side chains of the building units. In the case of peptide I, the Ile amino acid residue exerts more steric crowding near the peptide backbone, which helps to form high-energy open structure conformers rather than low-energy β-turns (Table S1). Concomitantly, Ile amino acid residue in peptide I reduces steric crowding at the periphery, which helps other building units come closer. Selfassociation of open structure and type-III β-turn conformers of peptide I renders compact fitting among donor−acceptor sites of the building units resulting in significant enthalpic stabilization. Moreover, halogen bonding interactions (between CO(Aib(2)) of Mol B and I(4(I)Phe(1)) of Mol A) also contribute considerably to the overall enthalpic stabilization for the solid state rearrangement of peptide I. The reason why peptide III does not display ribbon-like organization unlike peptide I can be attributed to the electronic effects of the halide substituents. More electron withdrawing fluoride in peptide III than iodide in peptide I results in weaker packing stabilization (−0.17 eV per H-bonding for III vs−0.39 eV per H-bonding for I) among the building units for the former. Formation of ribbon-like association of solely β-type turn building units could render huge intermolecular steric repulsion. Similarly, the Leu residue in peptide II/IV reduces steric crowding near the peptide backbone facilitating exclusive formation of only a βtype turn conformer in the solid state (Figure S15). Once again, a more electron withdrawing azide group in peptide IV than

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CONCLUSIONS In summary, this report reveals the diversity in self-assembly propensities of a series of synthetic tripeptides, differing in terminal side chains. Peptide I displays a preference for a supramolecular ribbon-like architecture, resulting from the selfassembly of two different conformers present in the asymmetric unit. The simultaneous existence of two different torsion angles around the Aib residue generates two distinct conformers in peptide I that may favor the nucleation of ribbon-like architecture in hierarchical organization. A slight change in modification of any of the terminal side chains does not support the nucleation of this ensemble as has been illustrated by our systematic crystallographic analysis. Furthermore, this supramolecular heterogeneity is supported by our computational studies using DFT calculations. From a thermodynamic point of view, although the ribbon rearrangement renders huge entropy loss in peptide I, the process becomes feasible. This is because the overall enthalpy gain is largely compensated by the entropy loss, summing up to the thermodynamic minimum in peptide I. Henceforth the peptides display significant supramolecular and morphological heterogeneity in the solid state. Thus, the importance of co-operative steric interactions among the side chains of amino acid residues is emphasized in stabilizing a particular supramolecular architecture. This research may not only indicate effective candidates in protein modification but also assist in rational design of peptidomimetics. 2136



Article

Crystal structures, packing diagrams along different axes, H and 13 CNMR, and IR spectra of peptides I, II, and IV (PDF1, PDF2, and PDF3)

1

Accession Codes

CCDC 1059542−1059543 and 1059545 and contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/ data_request/cif, or by emailing [email protected]. uk, or by contacting The Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS A.D.K. wishes to thank UGC (F.4-(55)/2014(BSR)/FRP) and DST, New Delhi, India (Project No. SR/FT/CS-118/2013), for financial support. She also acknowledges Professor M. G. B. Drew, University of Reading, for extremely valuable suggestions in crystallography. S.G. thanks IISER Bhopal for fellowship. The authors would like to thank Mr. Amit Kumar Mondal for optical rotation measurements and Mr. Mohammad Moin for various help during manuscript preparation.

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(1) Sengupta, A.; Aravinda, S.; Shamala, N.; Muruga, P.; Raja, K. M.; Balaram, P. Org. Biomol. Chem. 2006, 4, 4214. (2) Das, A. K.; Banerjee, A.; Drew, M. G. B.; Ray, S.; Banerjee, A.; Haldar, D. Tetrahedron 2005, 61, 5027. (3) Dutt, A.; Frohlich, R.; Pramanik, A. Org. Biomol. Chem. 2005, 3, 661. (4) Dutt, A.; Drew, M. G. B.; Pramanik, A. Tetrahedron 2005, 61, 11163. (5) Dutt, A.; Dutta, A.; Mondal, R.; Spencer, E. C.; Howard, J. A. K.; Pramanik, A. Tetrahedron 2007, 63, 10282. (6) Haldar, D.; Drew, M. G. B.; Banerjee, A. Tetrahedron 2006, 62, 6370. (7) Haldar, D.; Drew, M. G. B.; Banerjee, A. Tetrahedron 2007, 63, 5561. (8) Haldar, D.; Maji, S. K.; Sheldrick, W. S.; Banerjee, A. Tetrahedron Lett. 2002, 43, 2653. (9) Banerjee, A.; Maji, S. K.; Drew, M. G. B.; Haldar, D.; Banerjee, A. Tetrahedron Lett. 2003, 44, 6741. (10) Banerjee, A.; Maji, S. K.; Drew, M. G. B.; Haldar, D.; Banerjee, A. Tetrahedron Lett. 2003, 44, 335. (11) Maji, S. K.; Haldar, D.; Drew, M. G. B.; Banerjee, A.; Das, A. K.; Banerjee, A. Tetrahedron 2004, 60, 3251. (12) Jana, P.; Maity, S.; Haldar, D. CrystEngComm 2011, 13, 973. (13) Sharma, A.; Goswami, S.; Rajagopalan, R.; Dutt Konar, A. Supramol. Chem. 2015, 27, 669. (14) Dutt, A.; Spencer, E. C.; Howard, A. J. K.; Pramanik, A. Chem. Biodiversity 2010, 7, 363. (15) Syud, F. A.; Stanger, H. E.; Gellmann, S. H. J. Am. Chem. Soc. 2001, 123, 8667. (16) Phillips, S. T.; Piersanti, G.; Bartlett, P. A. Proc. Natl. Acad. Sci. U. S. A. 2005, 102, 13737. (17) Berka, K.; Laskowski, R.; Riley, K. E.; Hobza, P.; Vondrasek, J. J. Chem. Theory Comput. 2009, 5, 982.

Figure 10. FE-SEM images of (a) peptide I; (b) peptide II; and (c) peptide IV.

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REFERENCES

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.5b01803. 2137



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Can Side Chain Interactions Nucleate Supramolecular Heterogeneity

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