In silico characterization of G protein-host receptor interactions in Bangladesh Nipah virus mutants toward...

Nipah virus (NiV) remains a lethal zoonotic pathogen with two major clades: NiV-Malaysia (NiV-M) and NiV-Bangladesh (NiV-B), representing a persistent global threat. While research has largely focused on NiV-M, NiV-B shows distinct pathogenicity, including higher mortality and increased human transmission. Molecular interactions, especially involving NiV-B attachment glycoprotein binding to host receptors, remain underexplored, prompting this study's focus. Thus, this study presents an in silico investigation of NiV-B attachment glycoprotein (AGP) mutations and their impact on binding to human ephrin receptors EFNB2 and EFNB3, key mediators of viral entry. Nineteen mutations in the NiV-B AGP globular head region were modelled to generate a mutant structure (AGP_MT), which was subjected to docking using HADDOCK, molecular dynamics simulations, and MM/PBSA binding free energy calculations. Compared to the wild-type AGP, the mutant showed stronger and more stable binding to both receptors. Principal component analysis and free energy landscape profiling indicated that these mutations modulate the dynamic flexibility and conformational stability of the receptor complexes, potentially contributing to enhanced viral infectiousness. Our computational characterization elucidates molecular mechanisms underlying NiV-B receptor specificity and offers critical structural insights. These findings lay the groundwork for in silico screening of small molecules or peptides targeting the AGP-EFNB interface, providing promising leads for therapeutic development against NiV infections. This study exemplifies how advanced computational pharmacology methods can bridge molecular virology and drug discovery, accelerating efforts to combat emerging viral threats.

The online version contains supplementary material available at 10.1007/s40203-025-00535-x.