Multi-Site Aggregation of p53: Insights from Self- and Co-Aggregation of Multiple Aggregation-Prone Regions

Abstract

Amyloid-like aggregation of p53 leads to the loss of its tumor suppressor function and the acquisition of direct oncogenic properties, thereby promoting cancer progression. Studies have shown that mutations in p53 cause the exposure of multiple aggregation-prone regions (APRs), which can initiate multisite aggregation. Understanding the aggregation patterns of these APRs is crucial for elucidating the molecular mechanisms of p53 aggregation pathology. Here, we employed all-atom and coarse-grain molecular dynamics (MD) simulations to investigate self- and coaggregation behaviors of four p53 aggregation-prone fragments: 107YGFRLGFL114 (called as P1), 194LIRVEGNL201 (P2), 250PILTIITL257 (P3) and 270FEVRVCAC277 (P4). Our simulation results suggest that self-aggregation propensity follows the order P3 > P1 ≈ P4 > P2, driven primarily by solvent-mediated hydrophobic effects for P3, π–π stacking and cation−π interactions for P1, and mixed salt-bridge and hydrophobic interactions for P4 and P2. In binary hybrid systems, P1 and P3 not only exhibit the strongest coaggregation propensity through shared hydrophobic characteristics, but also can recruit P4 or P2 into heterogeneous aggregates. In contrast, P2P4 system displays a comparatively weaker coaggregation behavior. Our results emphasize that the development of effective aggregation inhibitors targeting APRs should account for both their intrinsic self-aggregation tendencies and their potential for cooperative aggregation with other peptide fragments.