Exploring the temperature dependence of ß-hairpin peptide self-assembly

Herein, we study the role that hydrophobicity plays in the temperature-dependent self-assembly of a family of ß-hairpin peptide amphiphiles through the lens of thermally folding a protein from its cold-denatured state. This was facilitated by the development of new computational tools to measure solvent-accessible charge (SAC) and solvent-accessible hydrophobicity (SAH) at the resolution of atomic groups. Peptides in their disordered states are characterized by large SAH values that shift their thermal assembly transitions to observable temperatures, which is not possible for most native proteins, allowing comparisons amongst peptides to be made. We find that peptides with large SAH values assemble into ß-sheet-rich fibers at lower temperatures and at faster rates than peptides having smaller SAH values. This is consistent with peptide assembly being driven by the hydrophobic effect, which involves the release of ordered water from hydrophobic moieties during assembly. We also find that peptide SAH values correlate linearly with Tg, the midpoint of the transition defining monomeric peptide transitioning to fibrils, for peptides of similar charge. Interestingly, the data also suggest that although entropy drives assembly, the exact temperature at which the assembly transition takes place is likely influenced by additional thermodynamic considerations.

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