Engineering polypeptide folding through trans double bonds: transformation of miniature β-meanders to hybrid helices

Abstract

Utilization of conjugated double bonds to engineer the novel folded miniature β-meander type structures, single step transformation of miniature β-meanders into ααγ(4)-hybrid peptide 10/12-helices using catalytic hydrogenation, their solution and single crystal conformations are reported.

Secondary Structure Tuning of a Pseudoprotein Between β‐Meander and α‐Helical Forms in the Solid‐State

“…b-Meander is ap rotein super secondary structural motif wherein consecutive b-strands are anti-parallelly arranged, forming am ultiply-linked hairpin structure. [13] Fort he pericyclic 1,3-dipolar cycloaddition reaction between azide and alkyne,they have to be ideally in aparallel or anti-parallel orientation within athreshold distance for the effective head-on orbital overlap of their p-orbitals.I nt he crystal lattice of dipeptide 1,t hough molecules are head-totail aligned along the b-stack, azide and alkyne units of adjacent molecules are not in distances and geometries (d = 4.95 ; f = 121.78 8 and d = 6.5 ; f = 29.68 8)s uitable for their topochemical reaction (Figure 2e). Though the unfavourable geometry and distance (as per the static crystal structure of dipeptide 1)d on ot support any topochemical reaction, the azide can rotate around C À Nb ond and the propargyl group can rotate around N À CH 2 bond to reach ap arallel/antiparallel orientation provided such motions are sterically favourable.T he void analysis revealed that large voids are present in the crystal lattice,e specially around the azide and alkyne groups,suggesting the possibility of rotational motion (Figure S2).…”

“…Similar CD spectra have been reported for a b-meander-type structure in solution state. [13] Thus it could be concluded that polymerization has progressed along the H-bonded stacks of dipeptide 1 molecules to result in pseudoprotein having b-meander structure (Figure 5d).…”

“…[17] This change in structure is not unexpected as the reaction along the hydrogen-bonding direction would connect the termini of the monomers by triazole linkers,a nd it necessitates achange from sheet structure to b-meander-type structure,w here anti-parallel b-strands are connected by bturns. [13] To get further confirmation of such structural change,…”

Non‐classical Helices with cis Carbon–Carbon Double Bonds in the Backbone: Structural Features of α,γ‐Hybrid Peptide Foldamers

“…Furthermore, we have shown an unusual planar structure from 1:1 alternating α‐residues and E ‐vinylogous residues (Figure ) . By using mild catalytic hydrogenation, we transformed the unusual planar structure resulting from 1:1 alternating α‐residues and E ‐vinylogous residues and miniature β‐meanders into 12 [12‐atom H‐bond pseudocycle between C=O( i )⋅⋅⋅NH( i +3)] and 10/12 [alternating 10‐atom H‐bond pseudocycle and 12‐atom H‐bond pseudocycle between C=O( i )⋅⋅⋅NH( i +3)] α,γ 4 ‐hybrid peptide helices, respectively . Since E ‐vinylogous amino acids promote β‐sheet structures in hybrid peptides, we hypothesized that the geometrical constraints of Z ‐vinylogous amino acids could be utilized to design helical structures.…”

“… A) The unusual planar structure resulting from 1:1 alternating α‐residues and E ‐vinylogous residues (Boc‐Aib‐ E γPhe‐Aib‐ E γPhe‐OEt) . B) A miniature β‐meander mimetic consisting of an α,α,γ‐hybrid peptide (Boc‐Leu‐Aib‐ E γPhe‐Leu‐Aib‐ E γPhe‐OEt) . Aib=2‐aminoisobutyric acid.…”