Effects of Single Mutations on Protein Stability Are Gaussian Distributed

Area of Science:

• Biophysics
• Statistical Mechanics
• Protein Science

Background:

• Empirical studies show protein stability effects approximate a Gaussian distribution.
• Previous theoretical approaches relied on assumptions about residue proximity.

Purpose of the Study:

• To rigorously derive the Gaussian distribution of per-residue-position protein stability effects from first-principles statistical mechanics.
• To provide a more fundamental explanation for observed protein stability patterns.

Main Methods:

• Application of first-principles statistical mechanics.
• Derivation of per-residue-position stability effects.
• Utilizing the large number of standard amino acids (20).

Main Results:

• Protein stability effects per residue position are rigorously derived as Gaussian.
• The derivation does not require assumptions on the number of spatially proximate residues.
• Results are validated using computational and experimental data on mutant protein stabilities.

Conclusions:

• The Gaussian distribution of protein stability effects is a fundamental consequence of statistical mechanics.
• This provides a robust theoretical foundation for understanding protein stability variations.
• The findings are broadly applicable across all protein residue types.