An Orthogonal Computational Framework Identifies a Conserved RNA Motif in the SARS-CoV-2 Spike Gene
Abstract
Background: : Structured RNA elements in viral genomes are underexplored therapeutic targets, yet coding regions have not been systematically screened for conserved, structurally defined motifs.
Methods:: We screened the SARS‑CoV‑2 spike coding sequence across eight major variants using a staged pipeline combining thermodynamic scanning, secondary‑structure cross‑validation between physics‑based and deep‑learning predictors, tertiary prediction across seven tools with decoy‑controlled analogy searches, comparison with genome‑wide chemical‑probing data from three laboratories, and molecular dynamics simulation.
Results:: The screen identified three conserved, window‑robust loci at functionally important spike regions: near the N343 glycosylation site (Region A), the E484 receptor‑binding motif (Region B), and the S2′ cleavage site (Region C). Only Region A satisfied all thermodynamic and structural criteria, with a dinucleotide‑shuffle z‑score of −3.39 (p = 0.020), near‑identical secondary structure between RNAfold and MXfold2 (F1 = 0.99), and a best‑supported tertiary fold from convergence of Boltz‑2 and AlphaFold3 (TM‑score_RNA = 0.53). In‑cell chemical‑probing supported Region A (F1 = 0.83–0.85; AUROC = 0.663–0.892), while Regions B and C failed. Probing data refined the predicted fold to a two‑helix architecture with a flexible middle segment, and molecular dynamics of the 101‑nt window revealed two individually stable domains (3′ stem‑loop RMSD = 2.58 ± 0.53 Å; 5′ helix…
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