Inhibition of the Early-Stage Cross-Amyloid Aggregation of Amyloid‑β and IAPP via EGCG: Insights from Molecular Dynamics Simulations

Amyloid-β (Aβ) and islet amyloid polypeptide (IAPP) are small peptides that have the potential to not only self-assemble but also cross-assemble and form cytotoxic amyloid aggregates. Recently, we experimentally investigated the nature of Aβ-IAPP coaggregation and its inhibition by small polyphenolic molecules. Notably, we found that epigallocatechin gallate (EGCG) had the ability to reduce heteroaggregate formation. However, the precise molecular mechanism behind the reduction of heteroaggregates remains unclear. In this study, the dimerization processes of Aβ40 and IAPP peptides with and without EGCG were characterized by the enhanced sampling technique. Our results showed that these amyloid peptides exhibited a tendency to form a stable heterodimer, which represented the first step toward coaggregation. Furthermore, we also found that the EGCG regulated the dimerization process. In the presence of EGCG, well-tempered metadynamics simulation indicated a notable shift in the bound state toward a greater center of mass (COM) distance. Additionally, the presence of EGCG led to a significant increase in the free energy barrier height (∼15k B T) along the COM distance, and we observed a transition state between the bound and unbound states. Our findings also unveiled that the EGCG formed a greater number of hydrogen bonds with Aβ40, effectively obstructing the dimer formation. In addition, we carried out microseconds of all-atom conventional molecular dynamics (cMD) simulations to investigate the formation of both hetero- and homo-oligomer states by these peptides. MD simulations illustrated that EGCG played a significant role in preventing oligomer formation by reducing the content of β-sheets in the peptide. Collectively, our results offered valuable insight into the mechanism of cross-amyloid aggregation between Aβ40 and IAPP and the inhibition effect of EGCG on the heteroaggregation process.