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Robust and Generic RNA Modeling Using Inferred Constraints: A Structure for the Hepatitis C Virus IRES Pseudoknot Domain

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journal contribution
posted on 22.06.2010 by Christopher A. Lavender, Feng Ding, Nikolay V. Dokholyan, Kevin M. Weeks
RNA function is dependent on its structure, yet three-dimensional folds for most biologically important RNAs are unknown. We develop a generic discrete molecular dynamics-based modeling system that uses long-range constraints inferred from diverse biochemical or bioinformatic analyses to create statistically significant (p < 0.01) nativelike folds for RNAs of known structure ranging from 45 to 158 nucleotides. We then predict the unknown structure of the hepatitis C virus internal ribosome entry site (IRES) pseudoknot domain. The resulting RNA model rationalizes independent solvent accessibility and cryo-electron microscopy structure information. The pseudoknot domain positions the AUG start codon near the mRNA channel and is tRNA-like, suggesting the IRES employs molecular mimicry as a functional strategy.