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

Abstract

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 (CV) 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 CV feature occurs, further analysis suggests that the amyloid-forming sequences exhibit the key CV feature at a lower temperature compared to control sequences derived from the same protein.

Energy landscapes and heat capacity signatures for peptides correlate with phase separation propensity

“…While there have been several attempts (Dzuricky et al , 2020 ; Simon et al , 2017 ) to guide the rational design of peptides useful for bioengineering applications, the present study presents a new perspective to design peptides with targeted phase separation behaviour. A related study provides links between the secondary structures that contribute to low-temperature features for monomers and dimers of hexapeptide sequences that are experimentally known to aggregate (Nicy and Wales, 2023 ). It is important to understand that we are not actually interested in the low-temperature behaviour of the heat capacity and that an accurate calculation is not required.…”