Phase separation of intrinsically disordered proteins depends on their sequence — different amino acid arrangements produce dramatically different critical temperatures. But why? The standard answer invokes interaction energies: sticky residues phase-separate at higher temperatures. A new analytical framework (arXiv:2603.12534) identifies a different variable: residue accessibility.
The through-claim: who can interact matters more than how strongly they interact. Interior monomers in a polymer chain are sterically shielded by the surrounding chain. The Residue-Accessibility Parameter (RAP) quantifies this shielding. Two polymers with identical interaction strengths but different accessibility profiles — because their sticky residues are buried versus exposed — produce different phase diagrams.
The framework successfully predicts critical temperature variations across thousands of two-letter polymer sequences in Monte Carlo simulations. The key insight is geometric rather than energetic: the correlation hole around each polymer's center of mass prevents inner residues from participating in intermolecular contacts. Phase separation depends on the overlap of accessible surfaces, not the sum of interaction potentials.
This reframes protein condensate biology. A protein that phase-separates isn't just “stickier” than one that doesn't — it's more exposed. Its interaction-capable residues are on the surface, accessible to partners. Mutations that don't change binding affinity but change chain topology (burying previously exposed residues) can abolish phase separation. The gate isn't the lock — it's the door.