Toward a quantitative theory of intrinsically disordered proteins and their function

Area of Science:

• Protein structure and function
• Biophysics
• Genomics

Background:

• A significant number of proteins are intrinsically disordered, lacking a stable 3D structure.
• The role of intrinsic disorder in protein function is not well understood, challenging the traditional structure-function paradigm.

Purpose of the Study:

• To develop a quantitative theory predicting the role of intrinsic disorder in protein structure and function.
• To investigate the implications of protein disorder on protein interactions and functional classes.

Main Methods:

• Analytical solutions of fundamental thermodynamic models for protein interactions.
• Genome-wide surveys of protein disorder across functional categories (Gene Ontology) and binding affinities.
• Analysis of binding affinities (K(d)) for prokaryotic and eukaryotic genomes.

Main Results:

• The theory predicts that catalytic and low-affinity binding proteins favor ordered structures.
• High-affinity binding proteins, predominantly in eukaryotes, can tolerate intrinsic disorder.
• Increasing protein disorder can tune binding affinity to enhance specificity in promiscuous interactions.

Conclusions:

• Natural selection optimizes protein function by acting on folding stability.
• Intrinsic disorder plays a tunable role in protein function, particularly in high-affinity binding and modulating specificity.
• The findings offer insights into the evolution of protein structure-function relationships.