Surveying biomolecular frustration at atomic resolution.

Area of Science:

• Biophysics
• Computational Biology
• Drug Discovery

Background:

• Biomolecules need specific interactions and stability for cellular function.
• Evolution balances stability with strategic frustration for motion and partner interaction.
• Minimally frustrated landscapes are crucial for protein function.

Purpose of the Study:

• To develop a framework for quantifying and localizing biomolecular frustration at atomic resolution.
• To correlate frustration patterns with biological function and protein-ligand interactions.
• To explore the application of frustration analysis in drug discovery for enhanced specificity.

Main Methods:

• Examining energy changes upon local environment modification at atomic resolution.
• Analyzing the statistics of these energy changes to map frustration.
• Extending frustration analysis to protein-ligand complexes.

Main Results:

• Patches of highly frustrated interactions correlate with critical biological sites.
• Drug specificity is linked to minimally frustrated binding pockets and funneled landscapes.
• Atomistic frustration analysis provides a quantitative measure of frustration.

Conclusions:

• Biomolecular frustration is a key determinant of function and interaction specificity.
• This framework enables precise localization of frustration within biomolecules.
• Atomistic frustration analysis offers a novel approach for designing more specific drugs.