Field-assisted interfacial passivation: Microwave-enhanced EGCG remodeling of amyloid-β42 aggregates.

Amyloid misfolding and self-assembly are central pathological events of Alzheimer's disease and related proteinopathies. Although soluble oligomers are widely considered as the primary toxic species, how therapeutic modulators alter toxicity-relevant aggregate surfaces remains poorly understood. Here, we combine cell viability assays, thioflavin T (ThT) aggregation kinetics, circular dichroism (CD), transmission electron microscopy (TEM), and atomistic molecular dynamics (MD) simulations to investigate how microwave-assisted Epigallocatechin gallate (EGCG) remodels Aβ42 aggregates. We show that microwave exposure markedly enhanced EGCG-mediated cytoprotection in BV2 microglial cells while concurrently suppressing the formation of canonical ThT-responsive amyloid species. MD simulations revealed that oscillating electric fields promote a constrained, interface-selective remodeling of protofibrillar-like aggregates rather than catastrophic depolymerization. In the initial trajectory pair, field assistance redistributed EGCG contacts across more surface residues, accompanied by reduced overall and hydrophobic protein-only solvent-accessible surface area. At a key hydrophobic interface identified by contact-occupancy analysis, the combined treatment decreased local water density and solvent accessibility, indicating reduced local hydration. We define this collective surface state- characterized by expanded EGCG coverage, reduced hydrophobic exposure, and diminished solvent accessibility - as interfacial passivation. Moreover, simulation analysis revealed that the field-assisted EGCG adsorption state remains stable for at least 500 ns after field removal, suggesting that the electric field facilitates formation of a kinetically stable surface-bound configuration. Together, these findings support field-assisted interfacial passivation as a possible mechanism for amyloid modulation and suggest that passivating toxicity-relevant aggregate surfaces, rather than achieving complete depolymerization, may represent a promising therapeutic strategy.