DOI: 10.1021/cg901581r
Construction of Supramolecular Helices and Breaking the Helicity by Forming Supramolecular β-Sheet Structures Using Suitable Self-Assembling Pseudopeptide Building Blocks
2010, Vol. 10 4716–4721
Samit Guha,† Michael G. B. Drew,‡ and Arindam Banerjee*,† †
Department of Biological Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700 032, India, and ‡School of Chemistry, The University of Reading, Whiteknights, Reading, RG6 6AD, U.K. Received December 16, 2009; Revised Manuscript Received September 4, 2010
ABSTRACT: Bis-valine derivatives of malonamide (Guha, S.; Drew, M. G. B. Small 2008, 4, 1993-2005) and a bis-valine derivative of 1,1-cyclopropane dicarboxamide were used as building blocks for the construction of supramolecular helical structures. The six-membered intramolecular hydrogen-bonded scaffold is formed, and this acts as a unique supramolecular synthon for the construction of a pseudopeptide-based supramolecular helical structure. However, in absence of this intramolecular hydrogen bond, intermolecular hydrogen bonds are formed among the peptide strands. This leads to a supramolecular β-sheet structure. Proper selection of the supramolecular synthon (six-membered intramolecular hydrogenbonded scaffold) promotes supramolecular helix formation, and a deviation from this molecular structure dictates the disruption of supramolecular helicity. In this study, six crystal structures have been used to demonstrate that a change in the central angle and/or the central core structure of dicarboxamides can be used to design either a supramolecular helix or a β-sheet.
Introduction Helicity is a unique feature that has been found in nature. Examples of helicity include R-helical structures in proteins, the DNA double helical structure and triple helical structures in collagen proteins. Being inspired by this naturally occurring structural motif, chemists have successfully synthesized unimolecular and supramolecular helical structures.1 Various noncovalent interactions including electrostatic, hydrogen bonding, π-π stacking, van der Waals and water-mediated hydrogen bonding interactions have been utilized to form specific supramolecular structures using the knowledge of supramolecular chemistry.2 There are numerous examples of building up supramolecular helical structures from suitable molecular scaffolds. Significant efforts have been directed to construct supramolecular helices in non-natural systems using conformational restrictions in macromolecules, hydrogen bonding functionalities, and metal ion chelation.3 Gottarelli and co-workers reported that both cooperative effect of solvophobic interactions and hydrogen bonding have been exploited to make supramolecular helical architectures using 8-oxoguanosines in the liquid crystalline phase, in solution and at surfaces.4 This self-assembly into helical structures is completely different from that of the parent guanosines which, in the same experimental conditions, form flat, ribbon-like structures. Recently, Li and co-workers have reported the formation of a supramolecular helix from an amphiphilic pyrene derivative induced by a tryptophan residue and this helical structure is stabilized by electrostatic interactions.5 Ajayaghosh and co-workers have demonstrated that helicity can be induced from chiral to achiral molecules in hydrogenbonded supramolecular assemblies.6 However, the design and construction of supramolecular helicity using small peptide and pseudopeptide based building blocks are a formidable *To whom correspondence should be addressed. E-mail:
[email protected]. in. Fax: (þ) 91-33-2473-2805. pubs.acs.org/crystal
Published on Web 10/15/2010
task. Previous reports from our laboratory include design and construction of peptide/pseudopeptide based supramolecular helices,7 a supramolecular helix inside a supramolecular helix,8 enantiomeric supramolecular helices,9 supramolecular double helices,10 and supramolecular triple helices.11 However, the programming of supramolecular helicity using a suitable supramolecular synthon12,13 represents a challenging task, and to break the supramolecular helicity by changing the supramolecular synthon is even more challenging. In our previous study, we described two compounds, namely, bis-(N-R-amido-L-valine methyl ester)-malonate (VL-M-VL) and its mirror image bis-(N-R-amido-D-valine methyl ester)-malonate (VD-M-VD), and both of them are self-assembled to form supramolecular helical structures.9 In this paper, we report the construction of a similar type of supramolecular helix using a self-assembling short pseudopeptide building block, namely, bis-(N-R-amidoL L-valine methyl ester)-1,1-cyclopropane dicarboxylate (V -CPL V ), and this also supports our previous observations with a new cyclopropane core. So, regardless of the core, this can be generalized as a unique supramolecular synthon for supramolecular helix formation. Moreover, it is evident from this study that the helicity can be disrupted by using a different supramolecular synthon which forms a supramolecular β-sheet structure. This has been accomplished by using an achiral pseudopeptide, bis-(N-R-amido-R-aminoisobutyric acid methyl ester)-1,1-cyclobutane dicarboxylate (U-CB-U), and several chiral pseudopeptides including bis-(N-R-amido-L-valine methyl ester)1,1-cyclobutane dicarboxylate (VL-CB-VL) and its mirror image bis-(N-R-amido-D-valine methyl ester)-1,1-cyclobutane dicarboxylate (VD-CB-VD), bis-(N-R-amido-L-leucine methyl ester)-malonate (LL-M-LL) and its mirror image bis-(N-Ramido-D-leucine methyl ester)-malonate (LD-M-LD). This result further supports our previous findings.9 So, this study is set up to examine the scope of our previous observation and prediction by using these new cyclopropane and cyclobutane derivatives. r 2010 American Chemical Society
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Table 1. Crystallographic Data for Pseudopeptides VL-CP-VL, VL-CB-VL, VD-CB-VD, U-CB-U, LL-M-LL, and LD-M-LD formula formula weight crystal system space group a, A˚ b, A˚ c, A˚ β, deg Z Dcalcd, g cm-3 μ, mm-1 T, K λ, A˚ R1 wR2 CCDC No.
VL-CP-VL
VL-CB-VL
VD-CB-VD
U-CB-U
LL-M-LL
LD-M-LD
C17H28N2O6 356.41 monoclinic P21 9.1627(7) 9.0925(7) 12.0991(9) 107.045(7) 2 1.228 0.093 150(2) 0.71073 0.0387 0.1106 757599
C18H30N2O6 370.44 orthorhombic P212121 9.5232(17) 16.749(3) 25.991(5) 90 8 1.187 0.089 150(2) 0.71073 0.0831 0.1710 757600
C18H30N2O6 370.44 orthorhombic P212121 9.4918(4) 16.7607(10) 25.9209(17) 90 8 1.193 0.089 150(2) 0.71073 0.0819 0.1443 757601
C16H26N2O6 342.39 monoclinic C2/c 11.613(9) 16.260(13) 10.010(9) 99.718(10) 4 1.221 0.093 293(2) 0.71073 0.1029 0.2153 757602
C17H30N2O6 358.43 monoclinic C2 24.342(2) 8.2740(6) 9.8114(7) 91.086(7) 4 1.205 0.091 150(2) 0.71073 0.0365 0.0708 757603
C17H30N2O6 358.42 monoclinic C2 24.253(2) 8.2616(6) 9.7769(7) 90.930(7) 4 1.215 0.092 150(2) 0.71073 0.0706 0.2387 757604
Figure 1. (a, b) Various supramolecular synthons for supramolecular helix formation. (c) The reported six-membered intramolecular hydrogen bonded supramolecular synthon for the supramolecular helix formation. (d) The reported supramolecular synthon for the supramolecular β-sheet formation.
Experimental Section Pseudopeptide Synthesis. All pseudopeptides VL-CP-VL, VLCB-VL, VD-CB-VD, U-CB-U, LL-M-LL, and LD-M-LD were synthesized by conventional solution-phase methods through a racemization-free fragment condensation strategy (see Supporting Information). The C-terminus of the amino-acid residue was protected as a methyl ester. Couplings were mediated by dicyclohexylcarbodiimide/1-hydroxybenzotriazole (DCC/HOBt). Final compounds were fully characterized by 300 MHz 1H NMR spectroscopy, 75 MHz 13C NMR spectroscopy, DEPT 135, mass spectrometry, and FT-IR studies (see Supporting Information).
Results and Discussion Pseudopeptide VL-CP-VL, where 1,1-cyclopropane dicarboxylic acid (CP) is used as a central unit, pseudopeptides
VL-CB-VL, VD-CB-VD, and U-CB-U where 1,1-cyclobutane dicarboxylic acid (CB) is used as a central unit and pseudopeptides LL-M-LL, and LD-M-LD where malonic acid (M) is used as a central unit, were synthesized by conventional solution phase methodology, purified, and characterized. Crystals were grown from hot methanol/water (1:1) solution (Table 1).14 Previously reported compounds VL-M-VL and VD-M-VD individually forms a six-membered-turn-like molecular conformation, and this molecular scaffold is selfassembled further to form supramolecular helical structures.9 Our supramolecular helices are entirely different from Hirao’s reported supramoecular helix N,N/-bis{(S)-(þ)-1-methoxycarbonyl-2-(4-imidazolyl)ethyl}-2,6-pyridinedicarboxamide (LBHisPA) and the D-isomer (D-BHisPA)1c where two
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Guha et al. Table 2. Hydrogen-Bond Parameters in the Structures For Pseudopeptide VL-CP-VLa D-H 3 3 3 3 A H 3 3 3 3 A (A˚) D 3 3 3 3 A (A˚) D-H 3 3 3 3 A (deg) N2-H2 3 3 3 3 O5 1.83 2.670(2) 140 N6-H6 3 3 3 3 O3 (a) 2.22 3.115(2) 157 For Pseudopeptide VL-CB-VLb D-H 3 3 3 3 A N12A-H12A 3 3 3 3 O11B N12B-H12B 3 3 3 3 O11A(a) N6A-H6A 3 3 3 3 O5B(b) N6B-H6B 3 3 3 3 O5A
H3 3 3 3A (A˚)
D3 3 3 3A (A˚)
D-H 3 3 3 3 A (deg)
2.07 2.06 2.06 1.99
2.870(11) 2.847(11) 2.832(11) 2.822(11)
155 151 148 161
For Pseudopeptide VD-CB-VDc
Figure 2. ORTEP diagram with atomic numbering scheme of pseudopeptide VL-CP-VL. Ellipsoids are at 30% probability. A sixmembered intramolecular hydrogen bond is shown as a dotted line.
consecutive five-membered intramolecular hydrogen-bonded turns are used as the supramolecular synthon for a supramolecular helix formation (Figure 1a).1c An earlier report from our group includes the formation of supramolecular helices from tetrapeptides Boc-Phe-Aib-Ile-Aib-OMe and Boc-γ-Abu-AibLeu-Aib-OMe, where a double turn conformation acts as a supramolecular synthon (Figure 1b).7a In the case of supramolecular helix formation using 8-oxoguanosines, the cooperative effect of solvophobic interactions and hydrogen bonding have been exploited to form supramolecular helical architectures in different environments.4 However, in this study we report the formation of a supramolecular helix from a unique supramolecular synthon, a six-membered intramolecular hydrogenbonded turn (Figure 1c). The reported pseudopeptide VL-CP-VL in this study forms a turn-like molecular conformation involving a six-membered intramolecular hydrogen bond [N2-H2 3 3 3 3 O5dC5 (amide), 1.83 A˚] (Figure 2) (Table 2). It is then self-assembled to form a supramolecular helix through intermolecular hydrogen bonds [N6-H6 3 3 3 3 O3dC3 (amide), symmetry element 2 - x, 0.5 þ y, 1 - z] along the crystallographic c axis with a helical pitch length of 9.09 A˚ (Figure 3). Selected backbone torsional angles are given in Supporting Information, Table S1. The crystal structure of the pseudopeptide VL-CP-VL further revealed that individual supramolecular helical structures are regularly aligned via non-hydrogen bonding noncovalent interactions to form higher order supramolecular arrays along the crystallographic c axis (Supporting Information, Figure S25). The central core 1,1-cyclopropane dicarboxamide residue has been replaced by 1,1-cyclobutane dicarboxamide residues to probe whether they form supramolecular helix or not. Three pseudopeptides have been synthesized. They are bis-(N-R-amido-L-valine methyl ester)-1,1-cyclobutane dicarboxylate (VL-CB-VL) and its mirror image bis-(N-R-amido-Dvaline methyl ester)-1,1-cyclobutane dicarboxylate (VD-CBVD) as well as the achiral bis-(N-R-amido-R-aminoisobutyric acid methyl ester)-1,1-cyclobutane dicarboxylate (U-CB-U), in which the central core 1,1-cyclopropane dicarboxamide residue is substituted by the 1,1-cyclobutane dicarboxamide residue. Crystal structures of pseudopeptides VL-CB-VL and D V -CB-VD are mirror images to each other. Each of these pseudopeptides contains two molecules in the asymmetric unit (Figures S26 and S27, Supporting Information). It was interesting to note that crystals of the former pseudopeptide VL-CB-VL are of very poor quality and only a weak
D-H 3 3 3 3 A N6A-H6A 3 3 3 3 O5B(a) N6B-H6B 3 3 3 3 O5A N12A-H12A 3 3 3 3 O11B N12B-H12B 3 3 3 3 O11A(b)
H3 3 3 3A (A˚)
D3 3 3 3A (A˚)
D-H 3 3 3 3 A (deg)
2.02 2.01 2.09 2.04
2.824(3) 2.830(2) 2.875(3) 2.844(2)
154 158 152 155
For Pseudopeptide U-CB-Ud D-H 3 3 3 3 A H 3 3 3 3 A (A˚) D 3 3 3 3 A (A˚) D-H 3 3 3 3 A (deg) N23-H23 3 3 3 3 O22(a) 2.13 2.930(5) 154 For Pseudopeptide LL-M-LLe D-H 3 3 3 3 A H 3 3 3 3 A (A˚) D 3 3 3 3 A (A˚) D-H 3 3 3 3 A (deg) N12-H12 3 3 3 3 O21(a) 2.08 2.910(2) 162 N22-H22 3 3 3 3 O11 2.06 2.896(2) 162 For Pseudopeptide LD-M-LDf D-H 3 3 3 3 A H 3 3 3 3 A (A˚) D 3 3 3 3 A (A˚) D-H 3 3 3 3 A (deg) N12-H12 3 3 3 3 O21(a) 2.07 2.899(3) 162 N22-H22 3 3 3 3 O11 2.05 2.881(4) 162 a Symmetry elements: (a) 2 - x, 0.5 þ y, 1 - z b Symmetry elements: (a) 1 þ x, y, z; (b) -1 þ x, y, z. c Symmetry elements: (a) 1 þ x, y, z; (b) -1 þ x, y, z. d Symmetry elements: (a) x, -y, -0.5 þ z. e Symmetry elements: (a) x, y, -1 þ z. f Symmetry elements: (a) x, y, 1 þ z.
diffraction pattern could be obtained. Though data were measured up to 2θ of 60°, only data up to 40° were significant and refinement was carried out accordingly. In contrast to this data, data obtained from the compound VD-CB-VD were of good quality. In both molecules, conformations of the two independent molecules are significantly different as is evident from their respective torsion angles (Supporting Information, Table S1). The presence of a central cyclobutane unit, unlike the cyclopropane unit, brings about a major conformational change. The intramolecular hydrogen bond is no longer formed. Instead, intermolecular hydrogen bonds are formed. This leads to the formation of supramolecular β-sheets via molecular duplex formation involving N-H 3 3 3 OdC (amide) intermolecular hydrogen bonds along the crystallographic b axis (Figure 4) (Table 2).18 The achiral compound U-CB-U contains a crystallographic C2 axis at the central C1, and it does not form a six-membered intramolecular hydrogen bonded turn-like structure. However, it forms a flat extended molecular conformation (Figure S28a, Supporting Information), which on self-assembly leads to the formation of a supramolecular β-sheet structure involving N-H 3 3 3 OdC (amide) intermolecular hydrogen bonds (Figure S28b) (Table 2).
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Figure 3. (a) Schematic representation of supramolecular helix formation. (b and c) Stick model and space-filling model of pseudopeptide VL-CP-VL showing a hydrogen-bonded supramolecular helical structure along the crystallographic c axis.
Figure 5. (a) ORTEP diagram with atomic numbering scheme of pseudopeptide LL-M-LL. Ellipsoids are at 30% probability. (b) Stick model of pseudopeptide LL-M-LL showing a hydrogenbonded supramolecular β-sheet structure along the crystallographic c axis. Figure 4. (a, b) Stick models of pseudopeptides VL-CB-VL, and VD-CB-VD showing the hydrogen-bonded supramolecular β-sheet structures along the crystallographic b axis.
Previously reported bis-valine derivatives of malonamide VL-M-VL and VD-M-VD have been shown to form supramolecular helical structures. So, two related pseudopeptides, namely, bis-(N-R-amido-L-leucine methyl ester)-malonate (LL-M-LL) and its mirror image bis-(N-R-amido-Dleucine methyl ester)-malonate (LD-M-MD) have been synthesized to check whether the bis-leucine derivative of malonamide forms a six-membered intramolecular hydrogenbonded structure, which upon self-assembly forms a supramolecular helix or some other structures. Crystal structures of pseudopeptides LL-M-LL and LD-M-LD are mirror images with each other. Both of these pseuopeptides contain two molecules in the asymmetric unit (Figures 5a and 6a). However, they are significantly different in conformation, and it is shown by their torsion angles (Supporting Information, Table S1). Enantiomeric compounds LL-M-LL and LD-M-LD do not form the six-membered intramolecular hydrogen-bonded turnlike conformation. They form hydrogen-bonded supramolecular
Figure 6. (a) ORTEP diagram with atomic numbering scheme of pseudopeptide LD-M-LD. Ellipsoids are at 30% probability. (b) Stick model of pseudopeptide LD-M-LD showing a hydrogenbonded supramolecular β-sheet structure along the crystallographic a axis.
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β-sheet structures via molecular duplex formation involving N-H 3 3 3 OdC (amide) intermolecular hydrogen bonds along the crystallographic a axis (Figures 5b and 6b) (Table 2). It is noticeable that the lack of the six-membered intramolecular hydrogen bonded moiety leads to the formation of a flat molecular structure. This structure ultimately leads to the formation of a supramolecular β-sheet structure on self-association. The C-C-C (θ) angle of the central core of the dicarboxamide moiety (Figure 7) as well as six-membered intramolecular hydrogen bonding play an important role in the formation of a supramolecular helix. When the angle C-C-C (θ) is g114°, the six-membered intramolecular hydrogen bond is formed. This molecular conformation helps to make a supramolecular helical structure on self-assembly. Interestingly, this study and our previous results9 suggest that the lesser value of θ (θ
