When Physics Meets Biology: The role of structural heterogeneity and point mutations in intrinsically disordered proteins

One of the most significant advancements in structural biology has been the establishment of the structure-function paradigm, which links a protein's amino acid sequence to its folded 3D structure and subsequent biological function. While this paradigm has successfully elucidated diseases caused by point mutations and advanced targeted drug design, it is increasingly challenged by intrinsically disordered proteins and regions (IDP/Rs). These proteins lack a stable 3D structure, instead adopting highly flexible ensembles that facilitate diverse cellular interactions.Far from being niche, recent studies suggest that 50–70% of the human proteome includes functional IDRs critical to biological processes and disease. While the structural plasticity of IDP/Rs can be described using a polymeric, statistical mechanics formalism, such descriptions are often assumed to be immune to minor sequence perturbations. This raises a critical question: to what extent can IDP/R function be disrupted by mutations that preserve global physical descriptors? In this talk, I will present recent studies exploring the intersection of polymer science and IDP/R biophysics. I will demonstrate where the polymer-physics analogy holds, where it breaks, and which specific sequence details are most relevant in altering protein ensembles and biological outcomes.