Exploring the structural and functional dynamics of trimeric and tetrameric states of influenza encoded PB1-F2...

Influenza Viruses have always been a major health concern due to their highly contagious nature. The PB1-F2 viroporin encoded by the influenza A virus is known to be a pro-apoptotic protein involved in cell death induction of the host immune cells. The structural arrangement and the mode of action of PB1-F2 viroporin have not been fully understood yet. Nonetheless, there is limited information on the oligomeric state of PB1-F2 and its possible role in the pore formation which could act as a channel for ion transport. The probable oligomeric structural existences of the viroporin and their channel-like behavior need to be explored in light of experimental reports cited in the literature. In our study, we report on the structural and dynamical properties of the trimeric and tetrameric state of PB1-F2, investigated by molecular dynamics simulations with improved sampling of conformational states as the initial focus of the study is to establish a rationale for their existence in a lipid environment. The simulation study provides detailed information on the mitochondrial membrane permeation pathway which causes the leakage of mitochondrial contents like cytochrome C and induces apoptosis. By focusing on low-order oligomers, trimer, and tetramer, we have identified key pore-forming characteristics that serve as a foundation for understanding the pro-apoptotic activity of PB1-F2. The structural and dynamical properties of these states were evaluated in the light of experimental reports, which reveal the tetrameric form to be the preferable state in the lipid environment, demonstrating superior structural stability, effective channel symmetry, and ion permeation compared to the higher-order oligomers besides trimer including pentameric and hexameric assemblies. The simulation results also explore the typical ion transportation criteria based on finding a less energetic barrier for ions/water molecules crossing the membrane.