Extending the classical sequence–structure–function paradigm through protein dynamics and context‐dependent behavior

The traditional sequence-structure-function paradigm links biological activity to stable three-dimensional structures. However, growing evidence from intrinsically disordered proteins, intrinsically disordered regions, and phase-separating proteins indicates that many proteins function through dynamic conformational ensembles rather than fixed structures alone. These flexible systems adapt to their environments, enabling signal integration, allosteric modulation, and cellular regulation. Biomolecular condensates and dynamic protein assemblies coordinate biochemical activities through reversible, context-responsive interactions. We propose an expanded conceptual model: sequence → dynamics → conformational ensembles → context-dependent behavior. Rather than replacing the classical framework, this perspective serves as a complementary extension within a protein structure-function continuum model. This framework emphasizes conformational flexibility, ensemble redistribution, and cellular context as critical drivers of protein function, regulation, and disease.