Hydration plays a crucial role in the refolding of intrinsically disordered proteins into amyloid fibrils; however, the specific interactions between water and protein that may contribute to this process are still unknown. In our previous studies of alpha-synuclein (aSyn), we have shown that waters confined in fibril cavities are stabilizing features of this pathological fold; and that amino acids that hydrogen bond with these confined waters modulate primary and seeded aggregation. Here, we extend our aSyn molecular dynamics (MD) simulations with three new polymorphs and correlate MD trajectory information with known post-translational modifications (PTMs) and experimental data. Interestingly, we show that amino acids in cavities are more stably hydrated and more evolutionarily conserved than residues that are outside of cavities. Furthermore, amino acids in cavities that are post-translational modification sites have on average the longest protein-water hydrogen bond lifetimes (HBL). Utilizing the deep mutational screen dataset by Newberry et. al. and the Thioflavin T aggregation review by Pancoe et. al. parsed using a fibril cavity/non-cavity definition, we show that hydrophobic changes to amino acids in cavities have a larger effect on fitness and aggregation rate than residues outside cavities, supporting our hypothesis that these sites are involved in the inhibition of aSyn toxic fibrillization. Finally, we expand our study to include analysis of fibril structures of tau, FUS, TDP-43, prion, and hnRNPA1; all of which contained hydrated cavities, with tau, FUS and TDP-43 recapitulating our PTM results in aSyn fibril cavities.