Structural dynamics of Zika Virus NS1 via a reductionist approach reveal the disordered nature of its beta roll domain in isolation

Abstract

AbstractFlavivirus Non-structural 1 (NS1) protein performs multiple functions such as host immune evasion, interaction with complement system factors, membrane rearrangement, etc. Therefore, it is highly plausible that significant structural and folding dynamics of NS1 might play a role in its multifunctionality. The dimeric structures of NS1 of multiple flaviviruses, including Zika virus (ZIKV), are available. However, its domain-wise dynamics perspective has not been explored so far. Therefore, it is of utmost importance to understand the structural conformations of NS1 and its domains in isolation, possibly highlighting the implications on the overall NS1 protein dynamics. Here, we have employed extensively long molecular dynamic (MD) simulations to understand the role of monomer, dimer, and a reductionist approach in understanding the dynamics of the three structural domains (i.e., β- roll, wing, and β-ladder) in isolation. Further, we experimentally validated our findings using CD spectroscopy and confirmed the intrinsically disordered behavior of NS1 β-roll in isolation and lipid mimetic environments. We also found that the β-ladder domain is highly flexible during long simulations. Therefore, we believe this study may have implications for significant dynamics played by NS1 protein, specifically during oligomerization of NS1.Graphical AbstractSchematic representation of the ZIKV NS1 protein and the models that we have used in this study.