Stem-loop II motif (s2m) structural and dynamical differences between SARS-CoV-2 and b.1.617.2 (Delta) variant

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The stem-loop II motif (s2m) present in the 3'-untranslated region of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome differs from the B.1.617.2 (Delta) variant by one mutation (G15U). Preliminary bioinformatic and experimental results suggest a relationship between the Delta variant and the s2m G15U mutation. In addition, the G15U s2m secondary structure is unclear compared to known SARS-CoV-2 s2m base pairing, which could influence suspected viral lifecycle events. To define structural and dynamic differences, unbiased molecular dynamics simulations of the G15U s2m were carried out for 3.5 µs, using starting coordinates from our previously reported SARS-CoV-2 s2m model based on NMR NOE data. Simulations were carried out at 283 K, to match to NMR data, and 310 K, to match physiological conditions. Results from the 3.5 µs trajectories show significant differences in three-dimensional structure and secondary structure resulting in key tertiary motif changes through hydrogen bonding and base-stacking interactions in the terminal loop, stem, and bulges. In this work, structural and dynamical differences are defined between the wildtype SARS-CoV-2 and G15U s2m, enabling further analysis of the effects on possible lifecycle events and identification of new pharmacological antiviral targets. The stem-loop II motif (s2m) present in the 3'-untranslated region of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome differs from the B.1.617.2 (Delta) variant by one mutation (G15U). Preliminary bioinformatic and experimental results suggest a relationship between the Delta variant and the s2m G15U mutation. In addition, the G15U s2m secondary structure is unclear compared to known SARS-CoV-2 s2m base pairing, which could influence suspected viral lifecycle events. To define structural and dynamic differences, unbiased molecular dynamics simulations of the G15U s2m were carried out for 3.5 µs, using starting coordinates from our previously reported SARS-CoV-2 s2m model based on NMR NOE data. Simulations were carried out at 283 K, to match to NMR data, and 310 K, to match physiological conditions. Results from the 3.5 µs trajectories show significant differences in three-dimensional structure and secondary structure resulting in key tertiary motif changes through hydrogen bonding and base-stacking interactions in the terminal loop, stem, and bulges. In this work, structural and dynamical differences are defined between the wildtype SARS-CoV-2 and G15U s2m, enabling further analysis of the effects on possible lifecycle events and identification of new pharmacological antiviral targets.