Theoretical Insights into the Inhibitory Mechanism of EGCG-Functionalized Gold Nanoparticles on hIAPP Protofibrils

The self-assembly of human islet amyloid polypeptide (hIAPP) monomers into oligomers and fibrils is linked to the development of type 2 diabetes (T2D). The initial oligomers formed during this process are known to contribute to cell death in T2D. Therefore, inhibiting and destabilizing these oligomers is considered a potential therapeutic strategy for T2D treatment. Epigallocatechin gallate (EGCG) is one of the small molecules known for its anti-aggregation activities. However, its clinical application against amyloid-related diseases is limited due to poor chemical stability and low bioavailability. To overcome these limitations, the conjugation of small molecules with nanoparticles has shown promising results. In this study, we explored the anti-aggregation properties of EGCG-functionalized gold nanoparticles (EGCG_AuNP) against hIAPP using all-atom molecular dynamics simulations. For comparison, we also studied hIAPP in isolation. Our findings revealed that the structural stability of hIAPP was significantly affected by the presence of EGCG_AuNP. Specifically, we observed reduced β-sheet conformations, increased solvent-accessible surface area (SASA), and reduced hydrogen bonds (H-bonds) when EGCG_AuNP interacted with hIAPP. This study highlights polyphenol-functionalized gold nanoparticles as a promising strategy for targeting protein aggregates associated with T2D.