Abstract:
Mpox is a re-emerging zoonotic disease caused by the Mpox virus (MPXV),which poses a significant global health concern due to its increasing outbreaks and potential for severe complications in humans. The MPXV P2L protein is a key virulence factor that facilitates immune evasion by interfering with karyopherin-a2 (KPNA2)-mediated nuclear import of interferon regulatory factor 3 (IRF3). To explore the emergence and functional consequences of mutations in this protein, we analyzed 90 P2L protein isolates against the reference sequence (NP_536451.1). Multiple sequence alignment identified 13isolates with amino acid substitutions, including novel variants harboring multiple mutations such as P11S, E25D, D112F, and R119K. Computational stability analysis using I-Mutant 2.0, DynaMut2, m CSM, SDM, and DUET revealed that several substitutions, particularly E25D, M43C, A55T, andR119K, were consistently predicted to destabilize the protein. Further structural and functional assessments indicated that mutations such as D112F and V153Fdisrupted DNA binding, altered trans membrane topology, and modified key post-translational regulatory sites. Structural modeling of mutant proteins demonstrated conformational deviations from the wild type, with root-mean square deviation (RMSD) values ranging from 1.26-1.72 Å, underscoring mutation-induced alterations in protein folding. Molecular docking revealed that specific mutants, notably WJG54236.1 (P11S, E25D, D112F), exhibited enhanced binding affinity with KPNA2 compared to the wild type, accompanied by increased hydrogen bond and salt bridge interactions at the binding interface. These findings suggest that emerging mutations in P2L not only compromise protein stability but may also strengthen its inhibitory interaction with KPNA2,thereby amplifying MPXV’s immune evasion capacity. Collectively, this study highlights critical structural and functional impacts of novel P2L variants and provides a foundation for understanding their role in MPXV pathogenesis and therapeutic targeting.
Page(s):
154-154
DOI:
DOI not available
Published:
Journal: 1st International Conference on "Recent Advances in Green Biotechnology and Climate Resilience", September 15-16, 2025, Volume: 1, Issue: 1, Year: 2025
Keywords:
Mutation
,
Immune evasion
,
Amino acids of interferon regulatory factor 3 IRF3
,
MPOXV