Oligomerization Propensity Governs Self-Assembly Morphology: Insights from Steady-State Oligomer Analysis

Protein and peptide aggregation involves the transition from soluble species to β-sheet-rich aggregates through oligomeric intermediates. While mature aggregates are well-characterized, the mechanism governing the transition from isotropic spherical nuclei to diverse nanostructures remains unclear. Here, we investigate the self-assembly of five amphipathic peptides that form distinct nanostructures. Using oligomer-resolved ion mobility-mass spectrometry and molecular dynamics simulations, we reveal that the oligomerization propensity critically determines the morphological outcomes of peptide assembly. Oligomers formed at lower critical oligomerization concentrations promote nanofiber formation, while those stabilized at higher concentrations lead to nanoribbon assembly. Molecular dynamics simulations confirm that transitional oligomers exhibit minimal solvent-accessible surface areas and maximal hydrogen bonding. These findings establish the oligomerization propensity as a key determinant in directing peptide self-assembly pathways, providing design principles for engineering peptide-based nanostructures with controlled morphologies.