Membrane-binding properties of NS1 proteins from Zika and Dengue viruses: Comparative simulations in explicit bilayers reveal significant differences

Abstract

NS1 in flaviviruses is the only non-structural protein that is secretory and interacts with different cellular components. NS1 is localized in endoplasmic reticulum as a dimer to facilitate the viral replication. The crystal structures of NS1 homologs from zika (ZIKV) and dengue (DENV) viruses have revealed the organization of different domains in NS1 dimers. The {beta}-roll and the connector and intertwined loop regions of wing domains of NS1 have been shown to interact with the membranes. The membrane-binding properties and the differences between ZIKV and DENV NS1 homologs in interacting with the membranes have not been investigated. In this study, we have performed molecular dynamics (MD) simulations of ZIKV and DENV NS1 systems in apo and in POPE bilayers with different cholesterol concentrations (0, 20 and 40%). In the simulations with bilayers, the NS1 protein was placed just above the membrane surface. At the end of 600 ns production runs, ZIKV NS1 inserts deeper inside the membrane compared to the DENV counterpart. The conformational landscape sampled by NS1 in the presence of membrane was analyzed. Unlike ZIKV NS1, the orientation of DENV NS1 is asymmetric in which one of the chains in dimer interacts with the membrane while the other is exposed to the solvent. The {beta}-roll region in ZIKV NS1 penetrates beyond the headgroup region and some residues interact with the lipid acyl chains while the C-terminal region barely interacts with the headgroup. Specific residues in the intertwined region deeply penetrate inside the membrane with less interactions with water molecules. Our analysis showed that more charged residues of ZIKV NS1 are involved in stronger interactions with the headgroups than that found for DENV NS1. The role of hydrophobic and aromatic residues in interactions with acyl chain region is also evident. Presence of cholesterol affects the extent of insertion in the membrane and interaction of individual residues. This study clearly shows that the binding, insertion and interaction of ZIKV NS1 with the lipid bilayer significantly differs from its counterpart in DENV.