Can de-phosphorylation of serine-5 in the C-terminal domain of human polymerase II affect its interaction with the PA C-terminal domain of bat Flu A polymerase?

Influenza viruses depend on the host transcription machinery to create their new progeny viral mRNA. They need the host transcription machinery to hijack the 5'-capped RNA from the host RNAs in order to utilize them to activate their viral transcription. In this study, we computationally regenerated the interaction between 3 heptad repeats, phosphorylated at the fifth serine residue in each repeat, from human polymerase and the CT D of the PA subunit of viral RNA polymerase (Holo 3SEP). We also studied the effect of the de-phosphorylation of the Serine-5 in the middle heptad repeat on the stability of the interaction (Holo 2SEP). The dynamics of the protein association and the heptad repeat in both cases are studied using appropriate in silico tools. This is followed by applying the MM-GBSA method based on relative binding estimation to show the effect of the de-phosphorylation of the middle Serine-5. Results indicate a clear change in total relative binding energy in Holo 2SEP, compared to Holo 3SEP, with no shift in occupied amino acids involved in the interaction in both cases. Knowing that de-phosphorylation of one serine-5 has no significant contribution to the investigated interactions opens the door for further studies to understand the role of the middle heptad serine-5 in these interactions, as its dephosphorylation caused a decrease by approximate to 13% in the binding affinity values obtained using MM-GBSA. The current in silico study represents a one-step-ahead insight into the RNA-dependent RNA polymerase (RdRP) mechanism that is yet to be verified in the lab.Communicated by Ramaswamy H. Sarma

Automated summary

Influenza viruses rely on the host transcription machinery for their viral mRNA production. This study investigates the interaction between human polymerase and the PA subunit of viral RNA polymerase, specifically focusing on the effect of dephosphorylation on the stability of the interaction. The results show a clear change in binding energy upon dephosphorylation, suggesting the potential role of the middle heptad serine-5 in these interactions.