Modeling and structural studies of single-stranded RNA viruses
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My research focuses on structures of the genomes of single-stranded RNA viruses. The first project is concerned with the sequence and secondary structure of HIV-1 RNA. Based on the secondary structure that Watts et al. determined, I performed a series of analysis and the results suggested that the abundance of Adenosines at the wobble position of the codons leads to an unusual structure with numerous unpaired nucleotides. The findings indicated how the virus balances evolutionary pressures on the genomic RNA secondary structure against pressures on the sequence of the viral proteins. The second project is the modeling of satellite tobacco mosaic virus (STMV). STMV is a T=1 icosahedral virus with a single piece of RNA that has 1058 nucleotides. X-ray crystallography studies of this RNA have revealed a structure containing 30 helices. The linkers between the helices, the possible structures at the interior of the icosahedron, and the sequence of the RNA were all missing in the crystal structure. To explore how the genome is organized within the protein capsid, I built a 3D model based on the RNA secondary structure predicted by Susan Schroeder. Being the first all-atom model of any virus, this model is highly correlated with the crystal structure; and the comparison with the in vitro structure of the same RNA supports the hypothesis that capsid protein plays an important role in RNA folding during assembly. The third project includes the modeling of bacteriophage MS2 (MS2) and the examination of the compactness of RNA in different viruses. MS2 is a T=3 RNA virus, and the cryo-EM studies have revealed a double-shell conformation of the genome. My final model of MS2 recaptures the double-shell structure of the RNA presented in the cryo-EM density. In addition, the predicted secondary structure that I used for the construction of the model shares a strong similarity with the in vitro structure determined in 1980s. This similarity contrasts with the striking difference between in vivo and in vitro RNA structures observed in STMV. Inspired by this finding, I examined the compactness of the RNA of several different viruses. The results strongly suggest that the RNAs of viruses requiring packaging signals have evolved to be structurally compact, which facilitates post-replicational RNA packaging. In contrast, viruses that do not depend on packaging signals probably adopt co-replicational RNA packaging.