One Plus One Makes Three: Triangular Coupling of Correlated Amino Acid Mutations

Area of Science:

• Biophysics
• Computational Biology
• Protein Engineering

Background:

• Correlated mutations are key to protein fold prediction.
• Nonadditive mutation effects on protein stability and binding affinity are poorly understood.
• Physical mechanisms behind sequence correlations are elusive.

Purpose of the Study:

• To demonstrate statistical mechanics' capability in capturing nonadditive protein mutation effects.
• To identify short- and long-range thermodynamic couplings.
• To elucidate interaction pathways in staphylococcal nuclease mutations.

Main Methods:

• First-principles statistical mechanics calculations.
• Analysis of homologous protein sequences.
• Mutational studies on staphylococcal nuclease.

Main Results:

• Statistical mechanics accurately captures nonadditive mutation effects.
• Identified thermodynamic couplings include novel long-range correlations.
• Unraveled intricate interaction pathways driving mutation correlations.

Conclusions:

• First-principles statistical mechanics provides a robust framework for studying protein mutation nonadditivities.
• Understanding these couplings is essential for predicting and engineering protein behavior.
• The study reveals previously unknown long-range correlations and their underlying mechanisms.