Determination of amino acids that favour the αL region using Ramachandran propensity plots. Implications for α-sheet as the possible amyloid intermediate

Abstract

In amyloid diseases an insoluble amyloid fibril forms via a soluble oligomeric intermediate. It is this intermediate that mediates toxicity and it has been suggested, somewhat controversially, that it has the α-sheet structure. Nests and α-strands are similar peptide motifs in that alternate residues lie in the α_R and γ_L regions of the Ramachandran plot for nests, or α_R and α_L regions for α-strands. In nests a concavity is formed by the main chain NH atoms whereas in α-strands the main chain is almost straight. Using "Ramachandran propensity plots" to focus on the α_L/γ_L region, it is shown that glycine favours γ_L (82% of amino acids are glycine), but disfavours α_L (3% are glycine). Most charged and polar amino acids favour α_L with asparagine having by far the highest propensity. Thus, glycine favours nests but, contrary to common expectation, should not favour α-sheet. By contrast most charged or polar amino acids should favour α-sheet by their propensity for the α_L conformation, which is more discriminating amongst amino acids than the α_R conformation. Thus, these results suggest the composition of sequences that favour α-sheet formation and point towards effective prediction of α-sheet from sequence.

Keywords: Amyloid; Nest; Peptide plane flip; Ramachandran propensity plot; Repeating dipeptide conformation.