Deciphering the mucin defense mechanisms against SARS-CoV-2 using molecular simulations

Area of Science:

• Virology
• Structural Biology
• Immunology

Background:

• SARS-CoV-2 enters the respiratory tract through the mouth and nose.
• Mucins form the airway mucosal barrier, trapping viral particles.
• Mucin 1 (MUC1) may restrict SARS-CoV-2 entry, but its mechanism is unknown.

Purpose of the Study:

• Investigate the binding mechanism between MUC1 and SARS-CoV-2 Spike proteins (wild-type and variants).
• Elucidate the structural basis of MUC1's interaction with the Spike protein.
• Provide insights for developing new antiviral therapies.

Main Methods:

• Surface plasmon resonance and protein pulldown assays to confirm binding.
• Molecular docking to identify binding sites.
• Molecular dynamics simulations to analyze complex stability.
• Binding free energy calculations to quantify interaction strength.

Main Results:

• Direct binding confirmed between MUC1 and wild-type, Delta, and Omicron Spike proteins.
• Wild-type Spike showed higher affinity for MUC1 than variants.
• Identified key Spike residues involved in MUC1 interaction.
• Demonstrated a decline in MUC1 binding strength from wild-type to variants.

Conclusions:

• MUC1 plays a role in mucosal defense against SARS-CoV-2.
• Variant Spike proteins exhibit reduced binding to MUC1.
• Findings offer a structural basis for MUC1-Spike interactions and inform antiviral drug design.