Comparative structural dynamics and lipid fingerprints of complete flavivirus particles from coarse-grained simulations

Flaviviruses are enveloped RNA viruses of major medical relevance whose mature particles share a conserved icosahedral architecture but differ in stability, antigenic accessibility and sensitivity to neutralization. How sequence variation and local protein organization modulate whole-particle dynamics and protein–membrane coupling remains difficult to address experimentally because viral envelopes are crowded, nanoscale and highly dynamic systems.

Here, we present a comparative coarse-grained molecular dynamics study of complete virus-like particles from Zika virus, dengue virus, Japanese encephalitis virus, West Nile virus and tick-borne encephalitis virus. Using a standardized multiscale workflow and the SIRAH force field, we performed multi-microsecond CG-MD simulations of complete flaviviral envelopes with identical membrane composition, temperature and ionic conditions. This design allows us to evaluate virus-specific dynamical signatures emerging from the protein shell and membrane confinement, rather than from lipid-composition differences.

Our analysis integrates protein-centered and membrane-centered descriptors. At the protein level, we quantify envelope and membrane protein dynamics, with emphasis on viral breathing, transient fusion-loop exposure and geometric rearrangements of antibody-relevant epitopes. At the membrane level, we evaluate area per lipid, thickness, curvature fluctuations and leaflet organization. In parallel, residue-resolved coordination-number maps and two-dimensional lipid-density fingerprints reveal preferential interactions between lipid headgroups, glycerol/backbone regions, acyl chains and specific domains of E and M, including stem and transmembrane regions.

Across the five flaviviruses, our simulations suggest that globally similar viral architectures can generate distinct dynamical and protein–lipid interaction fingerprints under equivalent membrane conditions. These differences highlight protein–lipid hotspots and symmetry-dependent environments that may contribute to particle stability, fusion-loop accessibility and conformational landscapes targeted by broadly neutralizing antibodies. Overall, this work supports a view of the flaviviral envelope as an integrated protein–membrane assembly, in which the viral membrane is not a passive scaffold but an active modulator of virion stability and functional accessibility.