Lipid Architecture in the Zika Virus.

Far from being passive barriers, viral membranes actively influence the mechanical properties and biological activity of viruses. Their lipid-protein composition forms a responsive interface that impacts how viruses assemble, remain stable, and interact with their surroundings. While the behavior of lipids and proteins in cellular membranes is well-described, their specific contributions within viral systems remain underexplored, largely due to nanoscale complexity and experimental limitations involved. Here, coarse-grained molecular dynamics simulations of Zika virus were analyzed to characterize lipid organization inside the virus. Lipid selectivity is strongly influenced by helix residue composition and depth of insertion into the membrane. The amphipathic EH-3 helix, for instance, preferentially coordinates with POPC but also establishes localized contacts with POPS through Lys and Ser residues, reflecting a balance between hydrophobic and electrostatic interactions. In contrast, the transmembrane ET-2 helix, dominated by hydrophobic residues, displays reduced lipid selectivity, with only peripheral serines showing a modest preference for POPS. Across the viral envelope, POPE contributes less to residue-specific coordination, while POPS participates in polar interactions that modulate the environment near positively charged residues. By shedding light on how lipids contribute to the architecture of the viral envelope and membrane, this work offers insights that deepen the understanding of viral particle integrity, guiding target membrane-dependent processes in antiviral design.