tetano
Editor, Senior Moderator
Phys Chem Chem Phys
. 2025 Sep 25.
doi: 10.1039/d5cp01778e. Online ahead of print. Selectivity mechanism of the PB2 cap-binding domain of influenza A and B viruses for methylated cap analogs: insights from MD simulations
Ye Xiao[SUP] 1 [/SUP], Jilong Zhang[SUP] 1 [/SUP], Ran Jia[SUP] 1 [/SUP]
Affiliations
The PB2 cap-binding domain (PB2[SUB]cap[/SUB]) of the influenza virus is considered an important target for blocking viral transcription due to its cap binding. The lack of the complex structures of PB2[SUB]cap[/SUB] with m[SUP]7[/SUP]GDP limits the exploration of the binding differences between the PB2[SUB]cap[/SUB] of influenza A and B viruses (FluA and FluB, respectively) with methylated cap analogs (m[SUP]7[/SUP]GTP and m[SUP]7[/SUP]GDP). In this study, based on the complex structures of FluA-D and FluB-D obtained using Discovery Studio 2.5 software and the crystal structures of FluA and FluB with m[SUP]7[/SUP]GTP (FluA-T and FluB-T), we investigated the binding of FluA and FluB with m[SUP]7[/SUP]GTP and m[SUP]7[/SUP]GDP by molecular dynamics simulations and MM-GBSA calculations. The results show that m[SUP]7[/SUP]GTP binding affinity is greater than that of m[SUP]7[/SUP]GDP for FluA and FluB, with a more pronounced affinity for FluA than that for FluB. The differences in the properties of the key residues of FluA (F323, H357 and N429) and FluB (Q325, W359 and S431) and the structures of the methylated cap analogs may explain the differences in binding abilities. Besides, the sandwich structure, π-π stacking interactions, and the electrostatic interactions between PB2[SUB]cap[/SUB] and methylated cap analogs are the key factors in stabilizing the positioning in the binding pockets. Our work could provide some valuable theoretical clues for the development of influenza virus PB2 inhibitors.
. 2025 Sep 25.
doi: 10.1039/d5cp01778e. Online ahead of print. Selectivity mechanism of the PB2 cap-binding domain of influenza A and B viruses for methylated cap analogs: insights from MD simulations
Ye Xiao[SUP] 1 [/SUP], Jilong Zhang[SUP] 1 [/SUP], Ran Jia[SUP] 1 [/SUP]
Affiliations
- PMID: 40996313
- DOI: 10.1039/d5cp01778e
The PB2 cap-binding domain (PB2[SUB]cap[/SUB]) of the influenza virus is considered an important target for blocking viral transcription due to its cap binding. The lack of the complex structures of PB2[SUB]cap[/SUB] with m[SUP]7[/SUP]GDP limits the exploration of the binding differences between the PB2[SUB]cap[/SUB] of influenza A and B viruses (FluA and FluB, respectively) with methylated cap analogs (m[SUP]7[/SUP]GTP and m[SUP]7[/SUP]GDP). In this study, based on the complex structures of FluA-D and FluB-D obtained using Discovery Studio 2.5 software and the crystal structures of FluA and FluB with m[SUP]7[/SUP]GTP (FluA-T and FluB-T), we investigated the binding of FluA and FluB with m[SUP]7[/SUP]GTP and m[SUP]7[/SUP]GDP by molecular dynamics simulations and MM-GBSA calculations. The results show that m[SUP]7[/SUP]GTP binding affinity is greater than that of m[SUP]7[/SUP]GDP for FluA and FluB, with a more pronounced affinity for FluA than that for FluB. The differences in the properties of the key residues of FluA (F323, H357 and N429) and FluB (Q325, W359 and S431) and the structures of the methylated cap analogs may explain the differences in binding abilities. Besides, the sandwich structure, π-π stacking interactions, and the electrostatic interactions between PB2[SUB]cap[/SUB] and methylated cap analogs are the key factors in stabilizing the positioning in the binding pockets. Our work could provide some valuable theoretical clues for the development of influenza virus PB2 inhibitors.