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The tripeptide glycyl-histidyl-glycine (GHG) self-assembles into long, crystalline fibrils forming a strong hydrogel ( G ′ ∼ 50 kPa) above a critical concentration of 40 mM upon the deprotonation of its imidazole group. Spectroscopic data reveal a mixture of helically twisted β-sheets and monomers to coexist in the gel phase. 

UV circular dichroism (UVCD) spectroscopy is a prominent tool for exploring secondary structures of polypeptides and proteins. In the unfolded state of these biomolecules, most of the individual residues primarily sample a conformation called polyproline II. Its CD spectrum contains a negatively biased positive couplet with a pronounced negative maximum below and a weak positive maximum above 200 nm. It is traditionally rationalized in terms of an excitonic coupling mechanism augmented by polarization effects. In this work, we carry out new time-dependent density functional theory calculations on the cationic tripeptide GAG in implicit and explicit water to determine the transitions that give rise to the observed CD signals of polyproline II and β-strand conformations. Our results reveal a plethora of electronic transitions that are governed by configurational interactions between multiple molecular orbital transitions of comparable energy. We also show that reproducing the CD spectra of polyproline II and β-strand conformations requires the explicit consideration of water molecules. The structure dependence of delocalized occupied orbitals contributes to the experimentally-observed invalidation of Flory's isolated pair hypothesis. 

Cationic glycylalanylglycine (GAG) self-assembles into a gel in a 55 mol% ethanol/45 mol% water mixture. The gel exhibits a network of crystalline fibrils grown to lengths on a 10 −4 –10 −5 m scale (Farrel et al. , Soft Matter , 2016, 12 , 6096–6110). Rheological data are indicative of a rather strong gel with storage moduli in the 10 kPa regime. Spectroscopic data revealed the existence of two gel phases; one forms below T = 15 °C (phase I) while the other one forms in a temperature range between 15 °C and the melting temperature of ca. 35 °C (phase II). We explored the reformation of the cationic GAG gel in 55 mol% ethanol/45 mol% water after thermal annealing by spectroscopic and rheological means. Our data reveal that even a short residence time of 5 minutes in the sol phase at 50 °C produced a delay of the gelation process and a gel of lesser strength. These observations suggest that the residence time at the annealing temperature can be used to adjust the strength of both gel phases. Our spectroscopic data show that the annealing process does not change the chirality of peptide fibrils in the two gel phases and that the initial aggregation state of the reformation process is by far more ordered for phase I than it is for phase II. In the gel phases of GAG/ethanol/water mixtures, ethanol seems to function as a sort of catalyst that enables the self-assembly of the peptide in spite of its low intrinsic propensity for aggregation.