“Crystal memory” Affects the Properties of Peptide Hydrogels – The Case of the Cyclic Tyr‐Tyr dipeptide

Abstract

In this work a relationship between the crystal form and morphology and rheological properties of peptide-based hydrogels is examined. We show, that under favorable circumstances a correlation between a starting solid material and a self-assembly processes in solution can exist, leading to different properties of a resulting soft matter. This observation, together with an in-depth analysis of the influence of stereochemistry of self-assembled (ll) and (dl) Tyr-Tyr cyclic dipeptides (cYY) on the observed relationship between gelation and crystallization allowed us to gain a deeper understanding of the peptide hydrogelation processes at a molecular level, using liquid state NMR, rheological studies and scanning electron microscopy. In the course of our studies, several crystal forms of (ll)-cYY has been discovered and described in details using single crystal X-ray diffraction, as well as advanced solid state NMR, X-ray diffraction of powders, thermal analysis, FTIR, circular dichroism and crystal structure prediction (CSP) calculations. Subsequently, we found that while (ll)-cYY easily assembles into hydrogels with different properties depending on the starting solid form, (dl)-cYY always precipitated as one crystal form in the tested conditions. Molecular-level justification for this observation is given.

Self-Assembly of Homo- and Hetero-Chiral Cyclodipeptides into Supramolecular Polymers towards Antimicrobial Gels

“…We chose DKP1 as reference for self-assembly and gelation in these two solvent systems ( Table 3 ). Heterochiral DKPs 2–4 inevitably led to the formation of precipitates in aqueous conditions, as reported for heterochiral cyclo(Tyr-Tyr) [ 27 ]. However, DKPs 2–3 gelled soybean oil with a minimum gelling concentration (mgc) of 30 mM ( Figure 5 ).…”

“…Aliphatic amino acids proved to be useful building blocks to obtain organogels [ 26 ]. The use of aromatic amino acids, such as Trp and Tyr, afforded both hydrogels and organogels [ 27 , 28 , 29 ], as did cyclo(Phe-Phe) and cyclo(Leu-Phe) [ 26 , 30 , 31 , 32 , 33 ]. Furthermore, the latter was also reported for hydrogelation in physiological solutions, including phosphate-buffered saline (PBS) and cell-culture medium [ 30 , 32 ], thus opening the way to biological uses.…”

“…However, heterochiral cyclodipeptides are seldom studied for their self-assembling ability into gels [ 27 ], with none reported thus far as successful examples of gelators. In this study, we thus selected heterochiral cyclo(Leu-Phe) enantiomers and heterochiral cyclo(Phe-Phe) to fill the knowledge gap, and tested their ability to gel, as well as their cytocompatibility in vitro, and their antimicrobial activity on S. aureus as compared against the bioactive homochiral cyclo(Leu-Phe) [ 41 ].…”