Coevolution-based prediction of key allosteric residues for protein function regulation

Area of Science:

• Biochemistry
• Computational Biology
• Structural Biology

Background:

• Allostery is crucial for biological processes, but predicting how distant mutations or effectors impact protein function remains challenging.
• Rational design of protein engineering and allosteric drugs is hindered by the difficulty in forecasting allosteric effects.
• Existing methods for identifying allosteric sites and residues are limited, necessitating novel computational approaches.

Purpose of the Study:

• To develop a novel computational method, KeyAlloSite, for predicting allosteric sites and key allosteric residues.
• To leverage evolutionary coupling models to identify functionally important allosteric sites and residues.
• To provide a tool for advancing protein engineering, allosteric drug design, and understanding protein evolution.

Main Methods:

• Developed KeyAlloSite, a computational method based on the evolutionary coupling model.
• Predicted allosteric sites by analyzing the coupling strength between allosteric and orthosteric sites.
• Identified key allosteric residues by comparing evolutionary coupling score differences within allosteric pockets relative to functional sites.

Main Results:

• Protein allosteric sites show stronger evolutionary coupling to orthosteric sites than non-functional sites.
• Key allosteric residues predicted by KeyAlloSite align with experimental data for proteins like BCR-ABL1, Tar, and PDZ3, and cancer mutations.
• KeyAlloSite successfully predicted key allosteric residues critical for enzyme catalysis, even those distant from the catalytic site.

Conclusions:

• Weak coevolutionary couplings contain significant information about protein allosteric regulation.
• KeyAlloSite offers a powerful computational approach for studying allosteric regulation, designing allosteric drugs, and engineering protein function.
• The method enhances the rational design of allosteric modulators and the engineering of enzymes for specific catalytic activities.