Abstract
Viruses rely on the precise packaging of their genomes within a capsid to execute essential life-cycle events, yet the principles governing genome structural organization in this confined environment remain elusive. Here, we reveal that hepatitis B virus (HBV) pregenomic RNA (pgRNA) exploits liquid-liquid phase separation (LLPS) inside the capsid to sculpt its architecture. Multiscale molecular dynamics (MD) simulations, supplemented by biochemical assays, show that pgRNA coalesces into a hollow, shell-like condensate along the inner capsid surface, with coexisting low- and high-density regions. Electrostatic interactions between pgRNA and the disordered C-terminal domain of capsid protein primarily govern condensate formation. LLPS drives the establishment of microphases composed of nematically aligned RNA hairpin arrays interspersed by domains rich in flexible single-stranded RNA linkers, achieving an optimal balance between structural order and dynamic flexibility. Intriguingly, although the ensemble-averaged pgRNA density exhibits icosahedral symmetry, individual simulation snapshots display pronounced heterogeneity, indicating symmetry breaking at the single-particle level. In addition, LLPS-induced hollow-shell architecture of pgRNA genome promotes long-range RNA base-pairing and enhances polymerase mobility, which may facilitate the functional dynamics of polymerase during reverse transcription. Our findings uncover a capsid-confined LLPS mechanism that orchestrates viral genome structure and dynamics, offering new targets for antiviral intervention.
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Data availability
All source data generated in this study have been deposited in the Figshare database (https://doi.org/10.6084/m9.figshare.29605127). The input files of MD simulation and representative trajectory files are available at https://box.nju.edu.cn/d/eb918ffb092246cf8971/. Source data are provided with this paper.
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Acknowledgements
The authors gratefully acknowledge Dr. Xin Wang of BASF for his technical support with the Atomic Force Microscopy (AFM) experiments. This work was supported by National Natural Science Foundation of China (Grant Nos. 12574224 to W.L., 12090052 to W.W., and 12347102 to W.L.), Basic Research Program of Jiangsu Province (BK20253050 to W.L.), and the grant of Wenzhou Institute, University of Chinese Academy of Sciences (WIUCASQD2021010 to W.L., WIUCASQD2022036 to Y.B.). The authors also thank the support from HPC Center of Nanjing University, e-Science center of Nanjing University, Nanjing Kunpeng&Ascend Center of Cultivation, and the Nanjing Key Laboratory for Cardiovascular Information and Health Engineering Medicine (funded by the Nanjing Municipal Health Commission) and its Jiangsu counterpart.
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W.L. and W.W. conceived the ideas and designed the work. Y.B. and Y.H. conducted the molecular dynamics simulations. H.P. and J.M. carried out the experiments. Y.W. and Y.C. contributed to the discussion. Y.B., W.L. and W.W. co-wrote the manuscript.
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Bian, Y., Pan, H., Mao, J. et al. Structural organization of HBV pgRNA genome driven by phase separation in capsid confinement. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69689-2
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DOI: https://doi.org/10.1038/s41467-026-69689-2
