While several polyphenols were found to either inhibit
or modulate
the aggregation of proteins implicated in neurodegenerative diseases,
such as Parkinson’s disease (PD), discrepant action mechanisms
have been reported. This, in addition to some polyphenols’
pan-assay interference compounds’ reputation, casts some doubts
concerning their therapeutic relevance. Here, we studied, through
molecular dynamics and enhanced sampling methods, the aggregation
of 11-mer peptides from the non-amyloid-β component, an aggregation-prone
domain of α-synuclein (α-syn) implicated in PD and other
synucleinopathies, in neat water and aqueous solutions of resveratrol
(RSV) and gallic acid (GA). Further, simulations of the complete protein
were carried out in aqueous urea, RSV, and GA solutions. Our results
show that peptide aggregation is not disrupted by either phenolic
compound. Thus, instead, intrusion of RSV and GA in the inter-peptide
region induces a peptide–peptide re-orientation, favoring terminal
interactions that manifest in the formation of barrierless solvent-separated
configurations. Moreover, although the (poly)phenols induce a pronounced
peptide dewetting at high concentrations, β-sheet-rich regions,
a hallmark of α-syn aggregation, are not disrupted. Thus, our
results indicate that, if anything, RSV and GA delay or modulate peptide
aggregation at high concentrations via the stabilization of solvent-separated
conformations as opposed to aggregation inhibition. Structural analysis
of the full protein, however, shows that the (poly)phenols induce
more extended conformations of α-syn, similar to urea, possibly
also influencing its aggregation propensity. However, opposite to
urea, the (poly)phenols reduce α-syn’s conformational
space, likely due to steric effects and a slowdown of the solvent
dynamics. These effects are concentration-dependent and possibly unattainable
at therapeutic-relevant concentrations. These results suggest that
the aggregation inhibition activity of RSV and GA in vitro should
involve, instead, either the non-covalent binding to oligomeric intermediates
or the stabilization of the monomer and/or oligomers through the formation
of covalent bonds of the respective quinones with α-syn. In
addition, the enhanced aggregation tendency of the peptides observed
here could be associated with the formation of non-toxic oligomers,
reported for some polyphenols.