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Delta SARS-CoV-2 s2m Structure, Dynamics, and Entropy: Consequences of the G15U Mutation
Joseph A Makowski1, Adam H Kensinger1, Caylee L Cunningham1
1Department of Chemistry and Biochemistry and Center for Computational Sciences, Duquesne University, Pittsburgh, Pennsylvania 15282, United States.
ACS Physical Chemistry Au
|October 2, 2023
Summary
The Delta SARS-CoV-2 variant’s s2m RNA structure is more linear and less stable than the original SARS-CoV-2, explaining differences in homodimerization. This study reveals key structural and thermodynamic changes in the Delta s2m motif.
Area of Science:
- Molecular Biology
- Virology
- Structural Biology
Background:
- The Delta SARS-CoV-2 variant possesses a single nucleotide mutation (G15U) in the stem-loop II motif (s2m) compared to ancestral SARS-CoV-2.
- Previous homodimerization experiments showed unexpected differences between SARS-CoV-2 and Delta SARS-CoV-2 s2m, necessitating investigation into underlying structural and thermodynamic changes.
Purpose of the Study:
- To investigate the structural, dynamical, and thermodynamic differences between the SARS-CoV-2 s2m and Delta SARS-CoV-2 s2m.
- To rationalize the observed differences in s2m homodimerization between the two SARS-CoV-2 variants.
Main Methods:
- Induced the G15U substitution in a reported SARS-CoV-2 s2m model.
- Performed 3.5 microseconds of unbiased molecular dynamics simulations at 283 K and 310 K.
- Analyzed secondary and tertiary structures, helical parameters, dynamics, and entropy.
Main Results:
- The Delta s2m adopted a more linear hairpin structure, lacking the characteristic L-shaped kink observed in SARS-CoV-2 s2m, due to corrected upper stem defects.
- Increased fluctuation in the Delta s2m palindromic sequence led to an estimated entropic penalty of 6.8 kcal/mol at 310 K compared to SARS-CoV-2 s2m.
- These structural and entropic differences explain the reduced spontaneous homodimerization and formation of fewer kissing dimers and extended duplexes in Delta s2m.
Conclusions:
- The reduced L-shape and increased palindromic entropic penalty in Delta s2m provide a mechanistic explanation for observed in vitro electrophoresis homodimerization differences.
- The study establishes a foundation for understanding the role of s2m structural and dynamic variations in the viral lifecycle.
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