Publication date: Jun 22, 2025

SARS-CoV-2 primarily infects hosts via the respiratory tract, with the mouth and nose as key entry sites. Mucins, essential components of the airway mucosal barrier, function as binding sites for viral adhesion and intercept viral particles as physical barriers. Mucin 1 (MUC1) has been reported to restrict SARS-CoV-2 entry into host cells, but its protective mechanism and structural basis remain unclear. This study employs multidisciplinary approaches to comprehensively investigate the binding mechanism and dynamic interaction details between MUC1 and both wild-type and variant SARS-CoV-2 Spike proteins. Surface plasmon resonance and protein pulldown confirmed the direct binding between MUC1 and Spike protein, with wild-type Spike exhibiting stronger affinity than Delta and Omicron variants. Molecular docking identified the binding sites and interaction types between MUC1 and Spike proteins, followed by molecular dynamics simulations to evaluate the stability and structural behavior of different Spike-MUC1 complexes. Binding free energy calculation and decomposition revealed the progressive decline in MUC1 binding strength from wild-type to Delta and Omicron variants, and identified the key Spike residues contributing to the interaction. This study first constructs MUC1-Spike interaction model to explore the structural basis of mucosal defense against SARS-CoV-2, offering new insights for antiviral drug development and clinical strategies.

Semantics

Original Article