Side-Chain-Driven Dual Structural System of Poly-Arylopeptide: Selective Helical Formation Derived from Aromatic Ring Flips on the Backbone

Abstract

A methodology for producing dual structural systems of macromolecules, which involves flipping the unsymmetrical aromatic rings on the main chain is presented. Previously, we reported a non-natural polypeptide containing an aromatic ring on the peptide backbone, called a poly “arylopeptide”. Herein, we used 2,6-naphthalene rings as axially unsymmetrical spacers, which has two geometrical isomers, anti and syn, to create dual structural properties. The miniscule energy difference between the two geometrical isomers can be amplified by incorporating the 2,6-naphthylene units into the polypeptide backbone, which creates a thermodynamic driving force for the formation of two specific global structures (i.e., 31-helix or 41-helix) biased toward one side geometrical isomer depending on the side chain. Additionally, the 31-helix can be switched to the 41-helix upon addition of a small amount of additives, indicating a conformational conversion from an identical sequence. The developmental dual helical systems exploit basic molecular geometry and can serve as a design platform for synthetic polymers.

Conformational Switch of Arylopeptide: Helix–Helix Transition Based on Side Chain Solvation

“…The CD spectra of poly‐1b exhibited a noticeable solvent effect, as shown in Figure a. According to a previous report, [ 12 ] the shape of the Cotton effect can be reproduced by the linear combination of the spectra of poly‐1b ( 3 1 ‐form ) and poly‐1a ( 4 1 ‐form ) in THF. In the case of ethanol, the estimated ratio of the 3 1 ‐form / 4 1 ‐form of poly‐1b was 45/55 (Figure 2a, dashed line).…”

“…Poly‐1a (R = ─C 12 H 25 ) and poly‐1b [R = ─(CH 2 CH 2 O) 3 CH 3 )] form two distinct global structures, the contracted 4 1 ‐helix and the expanded 3 1 ‐helix, respectively. [ 12 ] The relationship between the side chain and helical structure was examined to obtain insight about the folding selectivity. Initially, poly‐1 bearing two different alkyl chains were synthesized according to Scheme 2, and the CD spectra of the polymers were measured in THF ( Figure b).…”

“…In a previous study, density‐functional‐theory (DFT) and time‐dependent (TD)‐DFT calculations were conducted to understand the Cotton effect's origin. [ 12 ] The observed CD spectra were assigned to the 4 1 ‐form and 3 1 ‐form , the local structure of 4 1 ‐helix and 3 1 ‐helix. In the case of the newly synthesized poly‐1c , which had shorter alkyl chains (R = ─C 6 H 13 ) than poly‐1a , the CD signal intensity at 252 nm, derived from the 4 1 ‐form , was smaller than that of poly‐1a .…”

“…Polymerization was conducted according to the reported procedure. [12,15] To a mixture of molecular sieves 3A (MS 3A), Na 2 CO 3 (1.2 eq. ), monomer (1.0 eq.…”

“…[ 11 ] Although the resulting arylopeptide could not form hydrogen bonds between the monomer units, unlike natural polypeptide, the CD intensity originating from the helical structure increases nonlinearly as a function of the degree of polymerization, indicating cooperative convergence of plural conformers, resulting in the formation of helix. The arylopeptide ( poly‐1 ) containing the axially unsymmetrical 2,6‐napthylene spacer [ 12 ] creates a nearly isoenergetic dual structural architecture; extended ( P )‐3 1 ‐helix and contracted ( P )‐4 1 ‐helix, depicted in Scheme . These differences in these global structures occur due to the presence of two stable local structures, the 3 1 ‐form and the 4 1 ‐form , produced by the axially unsymmetrical spacer on the main chain.…”