The interface of protein structure, protein biophysics, and molecular evolution

Area of Science:

• Integrates protein structural biology, biophysics, molecular evolution, and population genetics.
• Focuses on mechanistic understanding of protein biochemistry and evolution.

Background:

• Current interdisciplinary protein modeling approaches are nascent.
• Existing models primarily focus on amino acid substitutions and static structures.

Purpose of the Study:

• To describe the state-of-the-art in interdisciplinary protein modeling.
• To highlight limitations of current models and propose future directions.
• To bridge the gap between computational modeling and experimental data.

Main Methods:

• Discusses the relationship between amino acid substitution, protein structure, function, and fitness.
• Considers complex mutational processes (insertions, deletions, domain rearrangements, circular permutations).
• Evaluates the role of intrinsically disordered proteins, protein geometry, and dynamics.

Main Results:

• Protein expression level significantly influences evolutionary rate.
• Selection at the messenger RNA (mRNA) level and interaction specificity are key factors.
• High-throughput experimental data and ancestral sequence resurrection are crucial for model validation.

Conclusions:

• Improved protein models require incorporating dynamics, complex mutations, and expression levels.
• Integration of computational modeling with experimental approaches is essential for advancing biological inference and prediction.
• Future models should consider a broader range of evolutionary factors for greater accuracy.