Aggregation of Chameleon Peptides: Implications of α-Helicity in Fibril Formation

We investigate the relationship between the inherent secondary structure and aggregation propensity of peptides containing chameleon sequences (i.e., sequences that can adopt either alpha or beta structure depending on context) using a combination of replica exchange molecular dynamics simulations, ion-mobility mass spectrometry, circular dichroism, and transmission electron microscopy. We focus on an eight-residue long chameleon sequence that can adopt an alpha-helical structure in the context of the iron-binding protein from Bacillus anthracis (PDB id 1JIG) and a beta-strand in the context of the baculovirus P35 protein (PDB id 1P35). We show that the isolated chameleon sequence is intrinsically disordered, interconverting between alpha helical and beta-rich conformations. The inherent conformational plasticity of the sequence can be constrained by addition of flanking residues with a given secondary structure propensity. Intriguingly, we show that the chameleon sequence with helical flanking residues aggregates rapidly into fibrils, whereas the chameleon sequence with flanking residues that favor beta-conformations has weak aggregation propensity. This work sheds new insights into the possible role of alpha-helical intermediates in fibril formation.