Dynamic Allostery in Regulated Entry of Newcastle Disease Virus into Host Cells

Abstract

Newcastle disease virus (NDV) belongs to the family of paramyxoviruses that cause numerous fatal diseases in humans and farm animals. Here we focus on mechanisms that underlie its regulated entry into host cells. To gain entry, NDV utilizes two of its membrane proteins: Hemagglutinin-Neuraminidase (HN) and the fusion (F) protein. HN binds to sialic acids expressed on the host cell, and this binding stimulates HN to activate F, which, in turn, mediates virus-host membrane fusion. HN interacts with sialic acid and F through separate sites located on two different domains, however, no models explain this allosteric coupling. In fact, the analogous mechanisms in other paramyxoviruses also remain undetermined. Starting with X-ray structures of HN‘s receptor binding domain (bound to sialic acid derivatives), we examine using molecular dynamics how sialic acid affects HN's receptor binding domain (RBD) as well as HN's RBD-RBD dimeric interface. We note first that sialic acid induces only minor structural changes in individual RBDs - an observation similar to proteins like GPCRs that are regulated by dynamic allostery. Despite inducing minor changes in individual RBDs, we find that sialic acid reorients the RBD-RBD interface, and that this reorientation contributes to HN stimulation. Finally, we note that the induced RBD-RBD reorientation is unlike what we observed in the case Nipah's HN homolog (Dutta et al. Biophys. J. 2016), suggesting that fusion stimulation mechanisms are not conserved across paramyxoviruses.