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

TL;DR

This paper develops an analytical statistical mechanical model to predict the binding affinities of sequence-specific fuzzy complexes formed by intrinsically disordered proteins, correlating well with simulations.

Contribution

It introduces a simple 'jSCD' parameter derived from sequence charge patterns that predicts IDP binding affinities, advancing understanding of fuzzy protein interactions.

Findings

The model's predictions align with explicit-chain simulations.

The 'jSCD' parameter effectively correlates with binding affinities.

The framework is computationally efficient and broadly applicable.

Abstract

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 hetero-dimeric 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 "jSCD" 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.