Exploring Host-Binding Machineries of Mycobacteriophages with AlphaFold2

Area of Science:

• Structural biology
• Virology
• Microbiology

Background:

• Over 12,000 mycobacteriophages are known, but their structure-function relationships remain poorly understood.
• Mycobacteria, including pathogens like M. tuberculosis, pose significant global health challenges due to antibiotic resistance.
• Mycobacteriophages are valuable tools for mycobacteria research, diagnostics, and therapy.

Purpose of the Study:

• To explore the architecture of host-binding machineries in seven Siphoviridae family mycobacteriophages.
• To investigate structure-function relationships of mycobacteriophage-host interactions.
• To leverage AlphaFold2 for analyzing complex viral assemblies.

Main Methods:

• Utilized AlphaFold2 (AF2) for structural analysis of mycobacteriophage host-binding machineries.
• Focused on representative mycobacteriophages infecting Mycobacterium smegmatis, M. abscessus, and M. tuberculosis.
• Compared structural features with phages infecting other Gram-positive actinobacteria.

Main Results:

• Highlighted modularity and structural diversity in siphophage host-binding machineries.
• Identified unique features in mycobacteriophages compared to other actinobacteria phages.
• Discovered brush-like, polyglycine-rich domains potentially acting as novel receptor-binding sites.
• Observed two additional adhesion proteins in five of the studied mycobacteriophages.

Conclusions:

• Mycobacteriophage host-binding machineries show unique adaptations for the mycobacterial cell envelope.
• Polyglycine-rich domains may be a distinctive feature of mycobacteriophage interactions.
• Structural insights provide a framework for developing phage-based biotechnological applications and understanding viral diversity.