Porous organic cages as inhibitors of Aβ₄₂ peptide aggregation: a simulation study

The aggregation of Aβ monomers into oligomers with β-sheet structures is an important cause of Alzheimer's disease (AD), while the Aβ₄₂ peptide is more toxic and prone to aggregate. It is of great significance to study the inhibition mechanism of Aβ₄₂ monomer aggregation and find excellent inhibitors for the treatment of AD. Research in recent years has focused on small molecule compounds and nanoparticles, but they all have certain limitations. As a new type of porous material, a porous organic cage (POC) has potential application feasibility in the biomedical field due to its unique physicochemical properties. In this work, molecular dynamics simulations were used for the first time to explore the interaction and conformational transformation of the Aβ₄₂ peptide in CC3 crystals with different morphologies (planar and spherical). The results show that the adsorption of the Aβ₄₂ peptide on different CC3 crystals is mainly achieved through strong van der Waals forces. During the simulations, the Aβ₄₂ peptide undergoes various degrees of structural changes. Compared to that in water, this binding induces more irregular structures, such as turns and 3-helices, and inhibits the production of β-sheets, while enhancing the overall backbone rigidity of the Aβ₄₂ peptide. The transformation analysis of peptide conformation is further complemented by free energy landscape and cluster analysis. These findings provide a strong basis for CC3 crystals as novel inhibitors to inhibit the toxicity and aggregation of the Aβ₄₂ peptide.