Modulation of polypeptide conformation through donor–acceptor transformation of side-chain hydrogen bonding ligands

Abstract

Synthetic polypeptides have received increasing attention due to their ability to form higher ordered structures similar to proteins. The control over their secondary structures, which enables dynamic conformational changes, is primarily accomplished by tuning the side-chain hydrophobic or ionic interactions. Herein we report a strategy to modulate the conformation of polypeptides utilizing donor–acceptor interactions emanating from side-chain H-bonding ligands. Specifically, 1,2,3-triazole groups, when incorporated onto polypeptide side-chains, serve as both H-bond donors and acceptors at neutral pH and disrupt the α-helical conformation. When protonated, the resulting 1,2,3-triazolium ions lose the ability to act as H-bond acceptors, and the polypeptides regain their α-helical structure. The conformational change of triazole polypeptides in response to the donor-acceptor pattern was conclusively demonstrated using both experimental-based and simulation-based methods. We further showed the utility of this transition by designing smart, cell-penetrating polymers that undergo acid-activated endosomal escape in living cells.

Betulonic acid derivatives inhibiting coronavirus replication in cell culture via the nsp15 endoribonuclease

“…29,30 We decided to fuse betulonic acid with a 1,2,3-triazole moiety, which has the unique property to both accept and donate hydrogen bonds. [31][32][33][34] These derivatives were synthesized by our recently developed and convenient "triazolization" method to prepare 1,2,3-triazoles from primary amines and ketones. [35][36][37][38] First, Jones oxidation was performed to convert betulin 1 into betulonic acid 2 (Scheme 1).…”

Stimuli-Responsive Polypeptides for Biomedical Applications

“…The hydrogen bonding pattern of 1,2,3-triazole moiety located at the middle of the side chains was changed from binary to unitary in acidic conditions because the nitrogen in the triazole was protonated, thereby forming the intact helical conformation at a low pH through the conversion of hydrogen bonding patterns within the side chains [24]. In detail, the hydrogen of the 1,2,3-triazole had an interaction with that of amide bonds in the polypeptide backbone at neutral pH, which resulted in the disruption of the helical formation [24]. Contrastively, the hydrogen donating ability was weakened by the protonation of the 1,2,3-triazole groups, giving rise to the intact helical formation [24].…”

“…In detail, the hydrogen of the 1,2,3-triazole had an interaction with that of amide bonds in the polypeptide backbone at neutral pH, which resulted in the disruption of the helical formation [24]. Contrastively, the hydrogen donating ability was weakened by the protonation of the 1,2,3-triazole groups, giving rise to the intact helical formation [24]. The pH-activated helical conformation strongly destabilized the plasma lipid membranes and then accelerated the escape of endosomes [24].…”

“…Contrastively, the hydrogen donating ability was weakened by the protonation of the 1,2,3-triazole groups, giving rise to the intact helical formation [24]. The pH-activated helical conformation strongly destabilized the plasma lipid membranes and then accelerated the escape of endosomes [24].…”

Porous Microstructured Surfaces with pH‐Triggered Antibacterial Properties

“…Due to the breath figures method, the hydrophilic and pH‐sensitive thiazole and triazole groups spontaneously segregate toward the surface. Therefore, the surface chemistry can be modified by variations of pH, as the thiazole and triazole groups shift from neutral at physiological pH to positively charged thiazolium and triazolium groups at acidic pH values (see Scheme 1 ). When the positive charge increases at the surface (acidic pH), their wettability and antimicrobial activity are augmented.…”