Mechanistic Role of Different Functional Groups in Inhibiting Tryptophan Self-Assembly: Comparison between Aromatic and Nonaromatic Hydroxyl Moiety-Rich Chemical Compounds.

Tryptophan (TRP) self-assembly is responsible for the development of several neurodegenerative disorders, such as hypertryptophanemia, for which effective therapeutics are still lacking. Although several experimental studies have demonstrated varying inhibitory efficacies of different functional moiety-rich compounds, the mechanistic role of individual functional groups while inhibiting the spontaneous self-assembly is still elusive. We have performed molecular dynamics simulations to explore different kinds of interspecies interactions between TRP and distinct functional groups present in experimentally studied aromatic and nonaromatic compounds with varying concentrations: tannic acid (TA), which contains both aromatic and hydroxyl moieties, and polyols, namely, sorbitol and mannitol, which contain no aromatic ring but only hydroxyl moieties. TA reduces TRP self-assembly more effectively than polyols, a difference not attributable solely to molecular size or multivalency. Quantitative analyses of different TRP-TA interactions, including π-π stacking between aromatic rings and H-bonding between respective hydroxyl moieties, reveal that lifetimes of π-π stacking are much higher than the H-bond lifetimes. Notably, the number and strength of π-π stacking interactions dominate over the H-bonding interaction in TA-mediated inhibition, although a large number of hydroxyl groups are present in TA. Consequently, TRP exhibits longer residence times in the vicinity of TA than polyols. Furthermore, TA weakens π-π stacking between TRP molecules, reducing TRP aggregation. The computed TRP-TA binding energy may therefore serve as a guide for evaluating the efficacies of other chemical compounds, demonstrating the importance of the aromatic ring in inhibiting the early stages of TRP oligomerization.