Analytical Theory for Sequence-Specific Binary Fuzzy Complexes of Charged Intrinsically Disordered Proteins

Intrinsically disordered proteins (IDPs) are important for biological functions. In contrast to folded proteins, molecular recognition among certain IDPs is fuzzy in that their binding and/or phase separation are stochastically governed by the interacting IDPs' amino acid sequences, while their assembled conformations remain largely disordered. To help elucidate a basic aspect of this fascinating yet poorly understood phenomenon, the binding of a homo or heterodimeric pair of polyampholytic IDPs is modeled statistical mechanically using cluster expansion. We find that the binding affinities of binary fuzzy complexes in the model correlate strongly with a newly derived simple joint sequence charge decoration parameter readily calculable from the pair of IDPs' sequence charge patterns. Predictions by our analytical theory are in essential agreement with coarse-grained explicit-chain simulations. This computationally efficient theoretical framework is expected to be broadly applicable to rationalizing and predicting sequence-specific IDP-IDP polyelectrostatic interactions.