Trinucleotide
bulges in RNA commonly occur in nature. Yet, little
data exists concerning the thermodynamic parameters of this motif.
Algorithms that predict RNA secondary structure from sequence currently
attribute a constant free energy value of 3.2 kcal/mol to all trinucleotide
bulges, regardless of bulge sequence. To test the accuracy of this
model, RNA duplexes that contain frequent naturally occurring trinucleotide
bulges were optically melted, and their thermodynamic parameters—enthalpy,
entropy, free energy, and melting temperature—were determined.
The thermodynamic data were used to derive a new model to predict
the free energy contribution of trinucleotide bulges to RNA duplex
stability: ΔG°37, trint bulge = ΔG°37, bulge + ΔG°37, AU + ΔG°37, GU. The parameter ΔG°37, bulge is variable depending upon the purine
and pyrimidine composition of the bulge, ΔG°37, AU is a 0.49 kcal/mol penalty for an A-U
closing pair, and ΔG° 37, GU is a −0.56 kcal/mol bonus for a G-U closing pair. With both
closing pair and bulge sequence taken into account, this new model
predicts free energy values within 0.30 kcal/mol of the experimental
value. The new model can be used by algorithms that predict RNA free
energies as well as algorithms that use free energy minimization to
predict RNA secondary structure from sequence.
Herpes simplex virus-1 (HSV-1) infection of the cornea leads to a potentially blinding condition termed herpetic stromal keratitis (HSK). Clinical studies have indicated that disease is primarily associated with recurrent HSK following reactivation of a latent viral infection of the trigeminal ganglia. One of the key factors that limit inflammation of the cornea is the expression of Fas ligand (FasL). We demonstrate that infection of the cornea with HSV-1 results in increased functional expression of FasL and that mice expressing mutations in Fas (lpr) and FasL (gld) display increased recurrent HSK following reactivation compared to wild-type mice. Furthermore, both gld and lpr mice took longer to clear their corneas of infectious virus and the reactivation rate for these strains was significantly greater than that seen with wild-type mice. Collectively, these findings indicate that the interaction of Fas with FasL in the cornea restricts the development of recurrent HSK.
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