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

Area of Science:

• Biochemistry
• Biophysics
• Computational Biology

Background:

• Intrinsically disordered proteins (IDPs) play crucial roles in biological functions.
• Unlike folded proteins, IDPs exhibit "fuzzy" molecular recognition, where binding and phase separation are stochastic and conformationally disordered.
• Understanding the principles governing IDP interactions is essential but challenging.

Purpose of the Study:

• To develop a theoretical framework for understanding the binding mechanisms of intrinsically disordered proteins.
• To elucidate the relationship between amino acid sequence and binding affinity in IDP complexes.
• To provide a computationally efficient method for predicting IDP-IDP interactions.

Main Methods:

• Statistical mechanical modeling using cluster expansion was employed to study the binding of polyampholytic IDP pairs.
• A novel parameter, "joint sequence charge decoration," was derived from the charge patterns of interacting IDPs.
• Coarse-grained explicit-chain simulations were used to validate the theoretical predictions.

Main Results:

• A strong correlation was observed between the binding affinities of binary fuzzy complexes and the "joint sequence charge decoration" parameter.
• The derived theoretical predictions showed essential agreement with results from explicit-chain simulations.
• The study identified a key sequence-dependent parameter governing IDP binding.

Conclusions:

• The developed theoretical framework offers a computationally efficient approach to rationalize and predict IDP-IDP polyelectrostatic interactions.
• The "joint sequence charge decoration" parameter provides a simple yet powerful tool for understanding fuzzy binding in IDPs.
• This work is expected to have broad applicability in the study of intrinsically disordered protein interactions.