RNA sequence changes predict cellular activity through conformational ensemble thermodynamics
This article describes a study where researchers systematically altered the HIV-1 TAR RNA sequence to change its propensity to adopt a functional versus inactive secondary structure. Using 1H CEST NMR without isotopic labeling, they quantified these structural propensities and found that minor sequence changes shifted the active-state propensity by approximately 500-fold. These propensities could quantitatively predict changes in protein binding and cellular transactivation, and could be inferred from secondary-structure prediction algorithms within a thermodynamic framework.
Key quotes
Despite advances in structure prediction from sequence, predicting cellular activity requires conformational ensembles that capture propensities to form functionally active states.
Minor sequence changes shift the active-state propensity by ∼500-fold, quantitatively predicting changes in protein binding and cellular transactivation.
These propensities could be inferred from secondary-structure prediction algorithms and incorporated into a thermodynamic framework to quantitatively predict how sequence changes alter protein-binding affinity and RNA cellular activity.
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