Energy Landscapes and Heat Capacity Signatures for Monomers and Dimers of Amyloid-Forming Hexapeptides

Amyloid formation is a hallmark of various neurodegenerative disorders. In this contribution, energy landscapes are explored for various hexapeptides that are known to form amyloids. Heat capacity ([Formula: see text]) analysis at low temperature for these hexapeptides reveals that the low energy structures contributing to the first heat capacity feature above a threshold temperature exhibit a variety of backbone conformations for amyloid-forming monomers. The corresponding control sequences do not exhibit such structural polymorphism, as diagnosed via end-to-end distance and a dihedral angle defined for the monomer. A similar heat capacity analysis for dimer conformations obtained using basin-hopping global optimisation shows clear features in end-to-end distance versus dihedral correlation plots, where amyloid-forming sequences exhibit a preference for larger end-to-end distances and larger positive dihedrals. These results hold true for sequences taken from tau, amylin, insulin A chain, a de novo designed peptide, and various control sequences. While there is a little overall correlation between the aggregation propensity and the temperature at which the low-temperature [Formula: see text] feature occurs, further analysis suggests that the amyloid-forming sequences exhibit the key [Formula: see text] feature at a lower temperature compared to control sequences derived from the same protein.