Expanding the conformational pool of cis-β-sugar amino acid: accommodation of β -hGly motif in robust 14-helix

Tendencies of forming stable helices of heterooligomers composed of alternating rigid cis-β -sugar amino acid and flexible β-hGly motifs have been investigated, using a combination of molecular mechanics, CD, FT-IR, and NMR techniques. The results show that the solution structures of these oligomers exist as robust right-handed 14-helices. Here, we examine the role of conformationally rigid cis-β -sugar amino acid in preorganizing the conformation of β-hGly to form the 14-helix. Our findings also show that a right-handed 14-helix can be formed with as few as four properly sequenced heterogeneous residues. These results represent the expansion of the conformational pool of sugar amino acid in the design of well-folded 14-helices, which can be used to develop β-peptides endowed with biological activity

Self-assembly of cyclic homo- and hetero-β-peptides with cis-furanoid sugar amino acid and β-hGly as building blocks

The design, synthesis and characterization of a new class of peptide nanotubes, self-assembled from cyclic homo- and hetero-β -peptides based on cis-furanoid sugar amino acid and β -hGly residues are described; these results represent the expansion of the conformational pool of cis β -sugar amino acids in the design of peptide nanotubes

Formation of left-handed helices in hybrid peptide oligomers with cis β-sugar amino acid and L-Ala as building blocks

Residue based control of specific helical folding is explored in hybrid peptide oligomers consisting of alternating L-Ala and cis-β-furanoid sugar amino acid (FSAA) residues as building blocks; two series of these hybrid oligomers are designed, synthesized and extensively characterized by using NMR, CD, FT-IR and MD simulation studies; results show the co-existence of left-handed 11- and 14/15-helical conformations in these short oligomers of Boc-(α/β) and Boc-(β/α) series

Oligomers of cis-β-norbornene amino acid: formation of β-strand mimetics

The oligomers of constrained cis-exo-β-norbornene amino acid were synthesised and characterised by extensive NMR, CD, IR and MD studies. The results showed the formation of both right and left handed consecutive 6-membered hydrogen-bonded strands for [2S,3R] and [2R,3S] enantiomers, respectively

Mechanistic studies of peptide self-assembly: transient α-helices to stable β-sheets.

The pathologic self-assembly of proteins is associated with typically late-onset disorders such as Alzheimer\u27s disease, Parkinson\u27s disease, and type 2 diabetes. Important mechanistic details of the self-assembly are unknown, but there is increasing evidence supporting the role of transient α-helices in the early events. Islet amyloid polypeptide (IAPP) is a 37-residue polypeptide that self-assembles into aggregates that are toxic to the insulin-producing β cells. To elucidate early events in the self-assembly of IAPP, we used limited proteolysis to identify an exposed and flexible region in IAPP monomer. This region includes position 20 where a serine-to-glycine substitution (S20G) is associated with enhanced formation of amyloid fibrils and early onset type 2 diabetes. To perform detailed biophysical studies of the exposed and flexible region, we synthesized three peptides including IAPP(11-25)WT (wild type), IAPP(11-25)S20G, and IAPP(11-25)S20P. Solution-state NMR shows that all three peptides transiently populate the α-helical conformational space, but the S20P peptide, which does not self-assemble, transiently samples a broken helix. Under similar sample conditions, the WT and S20G peptides populate the α-helical intermediate state and β-sheet end state, respectively, of fibril formation. Our results suggest a mechanism for self-assembly that includes the stabilization of transient α-helices through the formation of NMR-invisible helical intermediates followed by an α-helix to β-sheet conformational rearrangement. Furthermore, our results suggest that reducing intermolecular helix-helix contacts as in the S20P peptide is an attractive strategy for the design of blockers of peptide self-assembly