Computational insights into the binding of pimodivir to the mutated PB2 subunit of the influenza A virus

ABSTRACT

Influenza A virus (IAV) is reported to develop Pimodivir resistance because of multiple mutations within the Polymerase basic 2 protein (PB2) of IAV. The lack of a high-resolution structure of these PB2 mutants complexed with Pimodivir hinders efforts to understand the drug resistance. Here we decipher the binding differences of Pimodivir in the wild-type and mutant systems Q306H, S324I, S324N, S324R, F404Y, and N510 T of IVA PB2 using homology modelling, molecular dynamics, molecular docking, and density functional theory simulations. The key residues responsible for Pimodivir binding were identified as Glu361, Arg355, Arg332, His357, and Phe323. Those mutations, mainly N510 T, result in significant conformational changes of Pimodivir in the PB2 active site. As a result, the affinity of Pimodivir is significantly reduced in the N510 T system. The mutation effects are less pronounced in the other mutant systems. Dynamic cross-correlation matrix (DCCM) analyses suggest that the single-point mutation N510 T produces an allosteric effect on the ligand-binding domain, thus reducing ligand-binding affinity. The present study reveals how a single-point mutation modulates the Pimodivir binding in IAV PB2, which provides important insights into designing new Pimodivir analogues with better binding affinities.

KEYWORDS:

• Influenza virus A
• drug resistance
• polymerase basic 2 protein
• molecular dynamics simulations
• energy decomposition analysis

Acknowledgments

MA would like to thank Hibah Penelitian Dasar Tahun 2023 and the World Class Professor (WCP) Program Tahun 2022 from the Directorate General of Higher Education, Research and Technology, Ministry of Education, Culture, Research, and Technology, Republic of Indonesia.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The data supporting this study’s findings are available within the article and its supplementary material and from the corresponding authors upon reasonable request.

Additional information

Funding

C.W acknowledges the support by the New Jersey Health Foundation (PC 76-21) and the U.S. National Science Foundation under Grants NSF ACI-1429467/RUI-1904797, and XSEDE MCB 170088.