The Molecular Clock in the Evolution of Protein Structures.

Area of Science:

• Molecular Evolution
• Structural Biology
• Bioinformatics

Background:

• The molecular clock hypothesis assumes constant substitution rates in protein sequences, crucial for molecular evolution.
• Violations of the molecular clock are well-studied in protein sequences but not protein structures.
• Variations in selective or mutational pressures over time can cause molecular clock violations.

Purpose of the Study:

• To introduce a novel statistical test for assessing molecular clock violations.
• To conduct a large-scale assessment of molecular clock consistency in protein sequence and structure evolution.
• To investigate the relationship between functional changes and molecular clock violations in protein evolution.

Main Methods:

• Developed and validated a novel statistical test called Significant Clock Violations (SCV) using computer simulations.
• Performed a large-scale assessment of molecular clock violations across protein sequences and structures in three large superfamilies.
• Analyzed changes in protein function using Gene Ontology and InterPro terms.

Main Results:

• Molecular clock violations are generally consistent between protein sequence and structure evolution.
• Clock violations are typically larger and more significant in protein structure evolution compared to sequence evolution.
• Changes in protein function correlate with significant clock violations in structure evolution.
• A notable proportion of significant clock violations were detected in structure but not sequence evolution, indicating structural information's utility in detecting accelerated evolution and positive selection.
• Clock violations in closely related protein pairs were often significant in sequence but not structure evolution, suggesting structural constraints despite sequence changes.

Conclusions:

• Protein structures are more strongly constrained by natural selection (both negative and positive) than protein sequences.
• Protein structure evolution provides a more sensitive measure for detecting accelerated evolution and positive selection than sequence evolution alone.
• The study highlights the importance of considering protein structure alongside sequence data for a comprehensive understanding of molecular evolution.