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

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 alpha-sheet structure. Nests and alpha-strands are similar peptide motifs in that alternate residues lie in the alpha R and gamma L regions of the Ramachandran plot for nests, or alpha R and alpha L regions for alpha-strands. In nests a concavity is formed by the main chain NH atoms whereas in alpha-strands the main chain is almost straight. Using Ramachandran propensity plots to focus on the alpha L/gamma L region, it is shown that glycine favours gamma L (82% of amino acids are glycine), but disfavours alpha L (3% are glycine). Most charged and polar amino acids favour alpha L with asparagine having by far the highest propensity. Thus, glycine favours nests but, contrary to common expectation, should not favour alpha-sheet. By contrast most charged or polar amino acids should favour alpha-sheet by their propensity for the alpha L conformation, which is more discriminating amongst amino acids than the alpha R conformation. Thus, these results suggest the composition of sequences that favour alpha-sheet formation and point towards effective prediction of alpha-sheet from sequence.

Automated summary

In amyloid diseases, insoluble amyloid fibrils are formed via a soluble oligomeric intermediate that mediates toxicity. The structure of this intermediate, potentially with an alpha-sheet structure, is controversial. Studies on peptide motifs like nests and alpha-strands show preferences for certain chain conformations, with glycine favoring gamma L and charged/polar amino acids favoring alpha L, which may impact alpha-sheet formation.