Polyphenols at the Helm: Excited State Photophysics and Mechanistic Insights Into Protein-Aggregation Inhibition Through Ultrafast Studies.

Abstract

Understanding how small molecules modulate protein aggregation is pivotal for developing strategies against amyloid-related disorders. Polyphenols are promising modulators, yet the connection between their molecular photophysics and aggregation inhibition remains largely unresolved. In this article, femtosecond transient absorption spectroscopy has been employed to unravel the excited-state dynamics of some commonly used polyphenols, namely, Baicalein, EGCG, and Myricetin across varied environments-neat solvents, micelles and reverse micelles, and in the presence of globular and intrinsically disordered protein (in its native and aggregated forms). Excited-state intramolecular proton transfer (ESIPT) emerges to be highly sensitive to hydrogen-bonding, polarity, and local confinement, serving as a subpicosecond reporter of polyphenol-environment interactions. In protein systems, modulation of ESIPT dynamics signals environment-specific embedding of polyphenols within evolving protein landscapes. A unique tri-parameter correlation-linking binding affinities of the polyphenols to the native proteins, ESIPT lifetimes, and aggregation kinetics-reveals that inhibitory potency arises not from tight native binding but from selective engagement with aggregation-prone species. This work posits ESIPT as a sensitive molecular signature that links ultrafast photophysics to the functional inhibition of protein aggregation, providing new insights into how small molecules navigate complex biomolecular environments to regulate self-assembly pathways.