Breaking the “unbreakable” ZIKA virus envelope
The rapid spread of zika virus (ZIKV) and its association with microcephaly and Guillain-Barre syndrome have raised major concerns worldwide. Studies have shown that ZIKV can survive in harsh conditions, e.g. high fever; in sharp contrast to the dengue virus (DENV) of same Flaviviridae family. In spite of recent cryo-EM structures that showed similar architecture of the ZIKV and DENV envelopes, little is known of what makes ZIKV envelope so robust and unique. Here, we present a detailed analysis of the constituent raft-raft and protein-protein interactions on ZIKV and DENV envelopes to undermine their differential stability at near-atomic to atomic level using coarse-grained (CG) and all-atom (AA) molecular dynamics simulations. Our results from CG simulations show that, at high temperatures, ZIKV envelope retains its structural integrity, while DENV2 disintegrate through the formation of holes at 5- and 3-fold vertices. Protein structural network from AA simulations shows a stronger inter-raft communications in ZIKV through multiple electrostatic and H-bond interactions. Particularly, the intricate network of interlocking DE-loop and FG-loop among five DIII domains in ZIKA vertices was exceedingly robust that makes this envelope stable, even at high temperatures. Our results are validated by alanine mutations to the CD-loop residues Gln350 and Thr351 that showed no effect on ZIKA stability, in close accordance with a recent mutagenesis study. These detailed information, which were difficult to extract experimentally, broadened our understanding of the flaviviruses and can accelerate the structure-based drug designing processes aiming ZIKA and DENV therapeutics.\n\nIMPORTANCEThe rapid spread of zika virus (ZIKV) and its association with severe birth defects have raised worldwide concern. Recent studies have shown that ZIKV can survive in harsh conditions, e.g. high fever, unlike dengue (DENV) and other flaviviruses. Here, we unravel the molecular basis of ZIKV unprecedented stability over DENV at high temperatures, mimicking fever. Our study, based on coarse-grained and all-atom molecular dynamics simulations, could not only explore the mechanism of DENV envelope breaking at high temperatures, but also captured atomic-level contacts and interactions at raft-raft and protein-protein interfaces that keep ZIKV envelope intact in similar conditions. The obtained results are validated by in-silico and reported in-vitro mutagenesis studies by showing the presence of specific H-bonding and electrostatic interactions among ZIKV E protein residues. At the end, our study was successful to define potential ZIKV epitopes and provide residue-level insights for designing specific ZIKV antibodies and small molecule inhibitors.