Delta SARS-CoV-2 s2m Structure, Dynamics, and Entropy: Consequences of the G15U Mutation.

Autor:	Makowski JA; Department of Chemistry and Biochemistry and Center for Computational Sciences, Duquesne University, Pittsburgh, Pennsylvania 15282, United States., Kensinger AH; Department of Chemistry and Biochemistry and Center for Computational Sciences, Duquesne University, Pittsburgh, Pennsylvania 15282, United States., Cunningham CL; Department of Chemistry and Biochemistry and Center for Computational Sciences, Duquesne University, Pittsburgh, Pennsylvania 15282, United States., Frye CJ; Department of Chemistry and Biochemistry and Center for Computational Sciences, Duquesne University, Pittsburgh, Pennsylvania 15282, United States., Shine M; Department of Biochemistry and Chemistry, Westminster College, New Wilmington, Pennsylvania 16172, United States., Lackey PE; Department of Biochemistry and Chemistry, Westminster College, New Wilmington, Pennsylvania 16172, United States., Mihailescu MR; Department of Chemistry and Biochemistry and Center for Computational Sciences, Duquesne University, Pittsburgh, Pennsylvania 15282, United States., Evanseck JD; Department of Chemistry and Biochemistry and Center for Computational Sciences, Duquesne University, Pittsburgh, Pennsylvania 15282, United States.
Jazyk:	angličtina
Zdroj:	ACS physical chemistry Au [ACS Phys Chem Au] 2023 May 17; Vol. 3 (5), pp. 434-443. Date of Electronic Publication: 2023 May 17 (Print Publication: 2023).
DOI:	10.1021/acsphyschemau.3c00008
Abstrakt:	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. Despite sequence similarity, unexpected differences between SARS-CoV-2 and Delta SARS-CoV-2 s2m homodimerization experiments require the discovery of unknown structural and thermodynamic changes necessary to rationalize the data. Using our reported SARS-CoV-2 s2m model, we induced the G15U substitution and performed 3.5 microseconds of unbiased molecular dynamics simulation at 283 and 310 K. The resultant Delta s2m adopted a secondary structure consistent with our reported NMR data, resulting in significant deviations in the tertiary structure and dynamics from our SARS-CoV-2 s2m model. First, we find differences in the overall three-dimensional structure, where the characteristic 90° L-shaped kink of the SARS-CoV-2 s2m did not form in the Delta s2m resulting in a "linear" hairpin with limited bending dynamics. Delta s2m helical parameters are calculated to align closely with A-form RNA, effectively eliminating a hinge point to form the L-shape kink by correcting an upper stem defect in SARS-CoV-2 induced by a noncanonical and dynamic G:A base pair. Ultimately, the shape difference rationalizes the migration differences in reported electrophoresis experiments. Second, increased fluctuation of the Delta s2m palindromic sequence, within the terminal loop, compared to SARS-CoV-2 s2m results in an estimated increase of entropy of 6.8 kcal/mol at 310 K relative to the SARS-CoV-2 s2m. The entropic difference offers a unique perspective on why the Delta s2m homodimerizes less spontaneously, forming fewer kissing dimers and extended duplexes compared to SARS-CoV-2. In this work, both the L-shape reduction and palindromic entropic penalty provides an explanation of our reported in vitro electrophoresis homodimerization results. Ultimately, the structural, dynamical, and entropic differences between the SARS-CoV-2 s2m and Delta s2m serve to establish a foundation for future studies of the s2m function in the viral lifecycle. Competing Interests: The authors declare no competing financial interest. (© 2023 The Authors. Published by American Chemical Society.)
Databáze:	MEDLINE
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