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Retinoic acid-inducible gene-I (RIG-I) is a cytosolic sensor protein that recognizes viral RNAs and triggers an innate immune response in cells. Panhandle-like base-paired blunt-ended 5' ppp/pp-dsRNA is a characteristic feature of viral RNAs. Structural studies of RIG-I C-terminal domain bound 5' ppp/pp-dsRNA complexes show the direct interaction between all the 5' terminal phosphates (α, β, and γ) and protein, suggesting γ phosphate might be a major recognition determinant for RIG-I binding. Biochemical studies, however, suggest that 5' pp-dsRNA is the minimal determinant for RIG-I binding and antiviral response. Despite biochemical and structural studies, the origin of viral RNA recognition by RIG-I is an unsolved problem. X-ray structures of RIG-I bound dsRNA not only provide atomic insight into the interaction network but also provide sufficiently good models for computational studies. We report structure-based molecular dynamics (MD) free energy calculations to quantitatively estimate the energetics of RIG-I binding to dsRNA containing 5' ppp, 5' pp, and 5' p. The results suggest that RIG-I weakly discriminates between 5' ppp-dsRNA and 5' pp-dsRNA (favoring former) and strongly disfavors 5' p-dsRNA with respect to the rest. Interestingly, direct interaction between γ phosphate of 5' ppp-dsRNA and RIG-I is a robust feature of the MD simulations. dsRNA binding to RIG-I is associated with Mg 2+ dissociation from the 5' phosphate/s of dsRNA. The higher Mg 2+ dissociation penalty from 5' ppp-dsRNA with respect to 5' pp-dsRNA offsets most of the favorable interaction between RIG-I and γ phosphate of 5' ppp-dsRNA. This leads to weak discrimination between 5' ppp-dsRNA and 5' pp-dsRNA. 5' p-dsRNA is discriminated strongly because of the loss of interaction with RIG-I.

Energetics of Preferential Binding of Retinoic Acid-Inducible Gene-I to Double-Stranded Viral RNAs with 5′ Tri-/Diphosphate over 5′ Monophosphate