Membrane Binding of Flaviviral Nonstructural Protein 1: Comparative Simulations of ZIKA and Dengue Virus NS1 Proteins in Pope Bilayers

Abstract

The rate of flavivirus infections has increased dramatically in the last few years, in particular infections due to the Dengue virus (DENV) and Zika virus (ZIKV). Hence better inhibition strategies against viral targets are required. One such target in the flaviviral family is the non-structural protein 1 (NS1). Upon infection, the NS1 dimers accumulate in ER lumen and transforms into a hexameric lipoprotein particle under severe disease conditions. Though the presence of dimers and hexamers have been proven, the membrane binding and lipoparticle formation process remains unexplored. This study investigates the membrane binding property of ZIKV and DENV NS1 proteins through all-atom molecular dynamics simulations. Since the NS1 dimers are the most prevalent in the lumen side of ER, the POPE membranes were modelled with varying cholesterol concentrations (0%, 20% and 40%). The 3.6 μs MD simulations clearly showed that ZIKV NS1 inserts deeper into the membrane than DENV NS1. In particular, the β-roll, wing domain and intertwined loop of ZIKV NS1 form the major membrane interacting regions. In this study, two conformations namely the stable membrane bound and solvent exposed conformations were observed for the previously uncharacterised intertwined loop. As ZIKV NS1 inserts more, it shows more number of interacting cholesterol molecules around than that found for DENV NS1. The variation in the number of basic/aromatic amino acids between ZIKV and DENV NS1 might influence their membrane insertion property and this has been quantified in our study. Altogether, our study forms the basis for understanding the membrane binding properties of flaviviral NS1 proteins and the functional characterization of the interacting regions.