Macromolecular crowding reshapes the conformational landscapes of intrinsically disordered proteins: mechanisms,...

Intrinsically disordered proteins (IDPs) populate heterogeneous conformational ensembles, making them particularly sensitive to the crowded intracellular environment. Defining how molecular crowding reshapes these ensembles is therefore essential for bridging in vitro biophysical observations with cellular function. Recent studies have shown that crowding does not simply drive non-specific compaction. Instead, it remodels IDP conformational ensembles through competing entropic, enthalpic and solvent-mediated contributions, giving rise to diverse and sequence-dependent outcomes. In this review, we summarize recent experimental and computational advances that reveal how distinct classes of crowders modulate IDP conformations and how these effects are further tuned in cellular environments. We also discuss the consequences of crowding-induced ensemble remodeling for molecular recognition, biomolecular phase separation, and aggregation. Together, these findings establish molecular crowding as a key determinant of IDP conformational landscapes and functional behavior in complex biological settings.