Sequence-encoded conformational biases shape 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: transient point-to-point contacts described by the sticker-and-spacer framework, and persistent surface-to-surface contacts proposed in the cross-β hypothesis. We investigated the molecular basis of these modes in the context of conformational biases, defined as sequence-encoded structural preferences of local segments. Using a five-residue model, we generated lag-series IDPs from the TIA-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. Their structural analyses revealed that strongly biased regions preferentially adopt extended structures, including β-strands, and the spacing between these regions influences metastable β-sheet formation. Our findings demonstrate that local conformational biases shape interaction modes of IDPs, thereby linking sequence to condensate properties and amyloid fibril formation.