Molecular Grammar of Intrinsically Disordered Regions: How Sequence and Context Shape Biomolecular Condensation and Disease

Intrinsically disordered regions (IDRs) are central components of many biomolecular condensates, where their sequence features help shape the weak and multivalent interactions underlying assembly and regulation. Aromatic and charged residues, sequence patterning, repeat motifs, and spacer properties can influence interaction tendencies and, in defined systems, phase behavior, molecular exchange, and material properties. Post-translational modifications can further tune these interactions. These sequence–interaction relationships provide a basis for the idea of an IDR “molecular grammar.” Here, we use this term specifically for experimentally supported relationships between sequence-level features and interaction tendencies, rather than for the broader cellular processes that organize complex assemblies. In cells, these tendencies operate within multicomponent systems involving nucleic acids, binding partners, stoichiometry, local concentration, and active biochemical processes. We examine how sequence-level molecular grammar contributes to biomolecular condensation and how these contributions are integrated into transcriptional regulation, chromatin organization, RNA metabolism, nucleolar organization, and disease-associated assemblies. We also discuss the evidence needed to connect phase behavior and molecular exchange with material properties and function and compare computational approaches that address different sequence- and assembly-related endpoints. Together, the current evidence supports a layered view in which molecular grammar describes sequence-encoded interaction tendencies, whereas cellular organization and function emerge from the broader molecular and biochemical context.