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Remdesivir (RDV) prodrug can be metabolized into a triphosphate form nucleotide analogue (RDV-TP) to bind and insert into the active site of viral RNA dependent RNA polymerase (RdRp) to further interfere with viral genome replication. In this work, we computationally studied how RDV-TP binds and inserts to the SARS-CoV-2 RdRp active site, in comparison with natural nucleotide substrate adenosine triphosphate (ATP). To do that, we first constructed atomic structural models of an initial binding complex (active site open) and a substrate insertion complex (active site closed), based on high-resolution cryo-EM structures determined recently for SARS-CoV-2 RdRp or non-structural protein (nsp) 12, in complex with accessory protein factors nsp7 and nsp8. By conducting all-atom molecular dynamics simulation with umbrella sampling strategies on the nucleotide insertion between the open and closed state RdRp complexes, our studies show that RDV-TP can initially bind in a comparatively stabilized state to the viral RdRp active site, as it primarily forms base stacking with the template uracil nucleotide (nt +1), which under freely fluctuations supports a low free energy barrier of the RDV-TP insertion (∼1.5 kcal mol −1 ). In comparison, the corresponding natural substrate ATP binds initially to the RdRp active site in Watson–Crick base pairing with the template nt, and inserts into the active site with a medium low free energy barrier (∼2.6 kcal mol −1 ), when the fluctuations of the template nt are well quenched. The simulations also show that the initial base stacking of RDV-TP with the template can be specifically stabilized by motif C-S759, S682 (near motif B) with the base, and motif G-K500 with the template backbone. Although the RDV-TP insertion can be hindered by motif F-R555/R553 interaction with the triphosphate, the ATP insertion seems to be facilitated by such interactions. The inserted RDV-TP and ATP can be further distinguished by specific sugar interaction with motif B-T687 and motif A-D623, respectively. 

The anomalous nondipolar and nonaxisymmetric magnetic fields of Uranus and Neptune have long challenged conventional views of planetary dynamos. A thin-shell dynamo conjecture captures the observed phenomena but leaves unexplained the fundamental material basis and underlying mechanism. Here we report extensive quantum-mechanical calculations of polymorphism in the hydrogen–oxygen system at the pressures and temperatures of the deep interiors of these ice giant planets (to >600 GPa and 7,000 K). The results reveal the surprising stability of solid and fluid trihydrogen oxide (H 3 O) at these extreme conditions. Fluid H 3 O is metallic and calculated to be stable near the cores of Uranus and Neptune. As a convecting fluid, the material could give rise to the magnetic field consistent with the thin-shell dynamo model proposed for these planets. H 3 O could also be a major component in both solid and superionic forms in other (e.g., nonconvecting) layers. The results thus provide a materials basis for understanding the enigmatic magnetic-field anomalies and other aspects of the interiors of Uranus and Neptune. These findings have direct implications for the internal structure, composition, and dynamos of related exoplanets.