Delta variant versus ancestral SARS-CoV-2 s2m dynamics and relative entropy.

Abstract

Bioinformatic analysis of the Delta SARS-CoV-2 genome reveals a single nucleotide mutation (G15U) in the stem-loop II motif (s2m) relative to ancestral SARS-CoV-2. However, the physical consequences of this change remains unexplained. Using our reported SARS-CoV-2 s2m model, we induced the G15U substitution and performed 3.5 microseconds of unbiased molecular dynamics simulation at each of 283 K and 310 K. The resultant Delta s2m adopted a secondary structure consistent with our NMR data, resulting in significant deviations in tertiary structure and dynamics from our SARS-CoV-2 s2m model. First, we find differences in three-dimensional structure, where the characteristic 90° L-shaped kink of the SARS-CoV-2 s2m never manifested in the Delta s2m (0°). Second, increased fluctuation of the Delta s2m palindromic sequence within the terminal loop results in an estimated increase of entropy of 6.82 kcal/mol at 310 K relative to the SARS-CoV-2 s2m. In this work, structural, dynamical, and entropic differences are defined between the SARS-CoV-2 s2m and Delta s2m, explaining the absence of a kissing homodimer band in our PAGE experiments and providing a foundation for future studies of s2m.