Elsevier

Tetrahedron

Volume 61, Issue 21, 23 May 2005, Pages 5027-5036
Tetrahedron

Can a consecutive double turn conformation be considered as a peptide based molecular scaffold for supramolecular helix in the solid state?

https://doi.org/10.1016/j.tet.2005.03.057Get rights and content

Abstract

Helices and sheets are ubiquitous in nature. However, there are also some examples of self-assembling molecules forming supramolecular helices and sheets in unnatural systems. Unlike supramolecular sheets there are a very few examples of peptide sub-units that can be used to construct supramolecular helical architectures using the backbone hydrogen bonding functionalities of peptides. In this report we describe the design and synthesis of two single turn/bend forming peptides (Boc-Phe-Aib-Ile-OMe 1 and Boc-Ala-Leu-Aib-OMe 2) (Aib: α-aminoisobutyric acid) and a series of double-turn forming peptides (Boc-Phe-Aib-Ile-Aib-OMe 3, Boc-Leu-Aib-Gly-Aib-OMe 4 and Boc-γ-Abu-Aib-Leu-Aib-OMe 5) (γ-Abu: γ-aminobutyric acid). It has been found that, in crystals, on self-assembly, single turn/bend forming peptides form either a supramolecular sheet (peptide 1) or a supramolecular helix (peptide 2), unlike self-associating double turn forming peptides, which have only the option of forming supramolecular helical assemblages.

Introduction

The challenge in molecular self-assembly is to design molecular building blocks that are predisposed to give definite supramolecular structures using non-covalent interactions. Supramolecular helices and sheets are the most common and indispensable form of structures in biological systems. Helicity exists in numerous biological and chemical systems. In proteins, the α-helical structure is a very common motif. In DNA-double helices,1 collagen triple helix2 and even in the coat protein complex of Tobacco Mosaic Virus (TMV),3 helicity is a common observable feature. Surprisingly, a considerable amount of helicity is also present in some misfolded, neurodegenerative disease-causing protein aggregates popularly known as amyloid plaques.4 Unnatural supramolecular helical structures can be constructed using conformational restriction of macromolecules,5 intra or intermolecular hydrogen bonds6 or by metal ion chelation.7 The most common and well-studied example of supramolecular single-, double- and triple-stranded helical conformations are metal chelated, self-assembled, oligonuclear coordination compounds,7 the helicates.8 Different approaches to construct supramolecular helices without metal ions and stabilized only by intermolecular and intramolecular hydrogen bonding have also been pursued.6, 9 Recently pyrene-4, 5-dione derivatives have been used to design supramolecular helical structures.10 Peptide derivatives11 and even chiral amino acids like the chiral 2,6-pyridinedicarboxamide containing the podand L-histidyl moieties and the corresponding D-derivative12a and ferrocene bearing the podand chiral dipeptide moieties (-L-Ala-L-Pro-OEt) and the corresponding D-derivative12b have been used to form supramolecular helical assemblages. Parthasarathi and his colleagues have synthesized and characterized a series of tripeptides which form extended helical structures with intervening water molecules between two consecutive peptide molecules and they demonstrated the hydrated helix pattern in crystals.13 Our group is involved in constructing supramolecular peptide helices utilizing the backbone hydrogen bonding functionalities of the peptide molecules.14 From our previous report, it has been observed that the short synthetic terminally blocked peptides with single turn/bend conformations can form either supramolecular sheets15 or supramolecular helices.14a However, the peptide molecules with a double turn structure, self-assemble to form supramolecular helices in crystals.14b–d Therefore, it is necessary to define the role of a consecutive β-turn structure in the formation of supramolecular helical architecture. In this context we have designed and synthesized a series of single and double turn/ bend forming peptides (Fig. 1). All our previously reported peptides14, 15 and the peptides described in the present work are listed in Table 1. In this paper, we address the question of whether self-assembling double-turn forming peptides can only form supramolecular helical structures or whether other supramolecular architectures are possible.

Section snippets

Results and discussion

Peptides (peptides 1, 2, 3, 4 and 5) reported in this study have been synthesized with conformationally constrained, helicogenic Aib (α-aminoisobutyric acid) residue(s) in order to induce the helical nature of the individual peptide backbone.16 The terminally protected tripeptides Boc-Phe-Aib-Ile-OMe 1 and Boc-Ala-Leu-Aib-OMe 2 (Fig. 1) have been designed and synthesized to obtain single β-turn/bend forming molecular conformations. The tetrapeptides Boc-Phe-Aib-Ile-Aib-OMe 3 and

Conclusion

All the reported peptides are composed of one or more conformationally constrained Aib residues and their backbone dihedral angles demonstrate that they mostly adopt helical conformations. Crystallographic studies of tripeptides 1 and 2 demonstrate that the self-association of peptides containing only one turn have two options to form a supramolecular architecture: either a supramolecular sheet or a supramolecular helix. Tetrapeptides 3 and 4 share a common structural motif, consecutive double

Boc-Phe(1)-OH 6

A solution of phenylalanine (4.95 g, 30 mmol) in a mixture of dioxane (60 mL), water (30 mL) and 1 M NaOH (30 mL) was stirred and cooled in an ice-water bath. Di-tert-butyldicarbonate (7.2 g, 33 mmol) was added and stirring was continued at room temperature for 6 h. Then the solution was concentrated under vacuum to about 40–60 mL, cooled in an ice water bath, covered with a layer of ethyl-acetate (about 50 mL) and acidified with a dilute solution of KHSO4 to pH 2–3 (Congo red). The aqueous phase was

Acknowledgements

We thank EPSRC and the University of Reading, U.K. for funds for the Image Plate System. S. Ray thanks the Council for Scientific and Industrial Research (C.S.I.R), New Delhi, India for financial assistance. This research is also supported by a grant from Department of Science and Technology (DST), India [Project No. SR/S5/OC-29/2003].

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