C-P.50: Unveiling Recurrent Binding Sites in H1N1 Nucleoprotein via Ensemble-Based Pocket Clustering
Authors
Anne-claude Camproux
Universite Paris Cite
Keywords
druggability prediction; residue-based clustering; molecular dynamics
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Influenza A nucleoprotein (NP) is a conserved multifunctional protein involved in RNA binding and oligomerization, making it an attractive antiviral target. However, static structures provide only a partial view of its ligandable regions, as conformational variability can alter pocket accessibility and predicted druggability.
Here, we characterized the binding site landscape of H1N1 NP using molecular dynamics simulations combined with ensemble-based pocket detection and residue-based clustering. Across 753 conformations, 16,404 detected pockets were clustered by residue composition to reconstruct recurrent binding site candidates and assess their recurrence and predicted druggability. Seven recurrent sites were retained based on recurrence and cluster-level predicted druggability and were further characterized according to residue-level organization, plasticity, and their position relative to NP–RNA and NP–NP interface regions. These sites displayed distinct structural behaviors, included stable compact NP head sites, RNA-interface-associated sites, and a dynamic extended site spanning the inter-domain groove. Comparison with the static reference structure distinguished stable, shifted, and dynamically emerging sites, including regions not apparent in the reference conformation.
Overall, this study provides an ensemble-based structural framework to reconstruct and prioritize recurrent ligandable regions in influenza A NP. By integrating recurrence, predicted druggability, site organization, and structural plasticity, it refines the description of NP binding sites in H1N1 and opens the way to ongoing comparative work with H5N1 NP to determine which recurrent binding sites are conserved, shifted, or subtype-specific across pathogenic influenza A subtypes.
Co-authors: Inés Sabine Rahali, Sandie Munier, Anne Badel, Delphine Flatters, Anne-Claude Camproux
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