Sequence-encoded conformational biases correlate with self-assembly modes of intrinsically disordered proteins.

Self-assembly of intrinsically disordered proteins (IDPs) underlies cellular functions and disease pathogenesis. This process is mediated by two intermolecular interaction modes: point-to-point contacts described by the sticker-and-spacer framework, and surface-to-surface contacts proposed in the cross-β hypothesis. In this study, we investigated the molecular basis of these modes in the context of conformational biases, defined as sequence-encoded structural preferences of local segments. To this end, employing a five-residue model as a mechanistic framework to capture local conformational biases, we designed lag-series IDPs from the T-cell intracellular antigen-1 prion-like domain by systematically modulating conformational biases while preserving amino acid composition. The lag-series IDPs demonstrated distinct condensate properties and varying capacities for amyloid fibril formation. The structural analyses suggested that strongly biased regions preferentially adopt extended structures, including β-strands, and the spacing between these regions influences metastable β-sheet formation. Our findings suggest that local conformational biases are associated with interaction modes of IDPs, thereby linking sequence to condensate properties and amyloid fibril formation.