Intrinsically disordered regions as drivers of protein aggregation: mechanisms, phase separation, and emerging predictive frameworks

Abstract

Intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) lack stable tertiary structures yet perform essential roles in cellular signaling, molecular recognition, transcriptional regulation, and biomolecular assembly. Their conformational flexibility enables functional adaptability but also increases susceptibility to aberrant intermolecular interactions and protein aggregation. Unlike folded proteins, aggregation in IDPs arises from transient conformational ensembles that expose cryptic aggregation-prone regions (APRs), facilitating oligomerization and fibril formation under specific cellular and environmental conditions. Several studies have further established a mechanistic relationship between intrinsic disorder, liquid–liquid phase separation (LLPS), and pathological aggregation, where dynamic condensates can undergo maturation into irreversible amyloid-like assemblies. These transitions are strongly influenced by sequence grammar, charge distribution, aromatic residue patterning, post-translational modifications, molecular crowding, and proteostasis regulation. This mini-review summarizes the molecular principles governing aggregation in disordered systems, with emphasis on conformational ensemble dynamics, disorder-to-order transitions, and the interplay between LLPS and fibrillization. The review further discusses computational approaches used to predict aggregation propensity in IDRs, including classical physicochemical predictors, ensemble-aware simulations, molecular dynamics frameworks, and emerging protein language model-based methods. Further, integration of artificial intelligence, structural biophysics, and multiscale modeling have substantially improved understanding of disorder-driven aggregation pathways. Collectively, these findings support a unified framework in which sequence composition, conformational heterogeneity, and cellular environment cooperatively regulate functional assembly and pathological aggregation in intrinsically disordered proteins.