C ₃ N Nanosheets Inhibit Aβ Dimerization in a Size-Dependent Manner

Alzheimer's disease (AD) has emerged as one of the most formidable and prevalent neurodegenerative disorders, posing a significant threat to global public health, particularly among the aging population. A growing body of evidence has established that the aggregation of amyloid-β (Aβ) peptides─especially in their oligomeric forms─plays a central neurotoxic role in the pathogenesis of AD. In recent years, 2D nanomaterials have demonstrated to effectively prevent or disrupt the Aβ oligomers. However, limited effort has been devoted to exploring how the size of 2D nanomaterials affects the antioligomerization of Aβ peptides. In this study, we employed all-atom molecular dynamics (MD) simulations to systematically investigate the effects of 2D C₃N nanosheets on the dimerization behavior of Aβ peptides, with a particular focus on the influence of nanosheet size. Our results reveal a pronounced size-dependent inhibitory effect of C₃N nanosheets on Aβ dimerization and β-sheet formation. Specifically, extensive analyses (including structural conformations, principal component analysis (PCA), secondary structures, residue-residue contact probabilities, hydrogen bonding, interaction between peptides and nanosheets, binding-free energies, and highlighted binding details) demonstrated that larger C₃N nanosheets with surface areas of 12.6 and 6.72 nm² were found to effectively suppress Aβ dimerization and prevent the emergence of β-sheet structures. In contrast, when the size of the C₃N nanosheet was reduced to 0.42 nm², its ability to inhibit Aβ dimerization and secondary structure formation became negligible. This difference in the inhibitory performance can be attributed to the available basal surface area of the C₃N nanosheets. Larger nanosheets are capable of accommodating entire Aβ peptides via surface adsorption, thereby spatially separating the peptides and hindering their aggregation. Conversely, the smallest nanosheet can bind only a limited number of peptide residues, leaving the remaining segments free to interact and assemble into β-sheet-rich structures. This work not only provides mechanistic insight into the molecular interactions between Aβ peptides and C₃N nanosheets and reveals the size-dependent inhibitory effect of C₃N nanosheets on Aβ dimerization but also highlights the potential of size-engineered C₃N nanomaterials as promising candidates for therapeutic intervention in Alzheimer's disease.