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

Adenine Methylation Enhances the Conformational Flexibility of an RNA Hairpin Tetraloop

“…Although the base flipping process is more frequently observed to proceed through the major groove in nucleic acids, it is not uncommon to observe purine nucleotides flipping via the minor groove pathway. 93,94 Tetraloop Adopts Conformations Conducive to Binding of the Reader Protein. A crystal structure of the A*UCG tetraloop bound to the reader (YTHDC1) protein shows that the tetraloop is recognized by the reader protein in a single-stranded conformation (Figure S10).…”