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Thermodynamic and structural characterization of 2'-nitrogen-modified RNA duplexes.

ABSTRACT: 2'-aminonucleosides are commonly used as sites of post-synthetic chemical modification within nucleic acids. As part of a larger cross-linking strategy, we appended alkyl groups onto the N2' position of 2'-amino-modified RNAs via 2'-ureido and 2'-amido linkages. We have characterized the thermodynamics of 2'-amino, 2'-alkylamido and 2'-alkylureido-modified RNA duplexes and show that 2'-ureido-modified RNAs are significantly more stable than analogous 2'-amido-modified RNAs. Using NMR spectroscopy and NMR-based molecular modeling of 2'-modified RNA duplexes, we examined the effects that 2'-nitrogen modifications have on RNA helices. Our data suggest that the 2'-ureido group forms a specific intra-nucleoside interaction that cannot occur within 2'-amido-modified helices. These results indicate that 2'-ureido modifications are superior to analogous 2'-amido ones for applications that require stable base pairing.

SUBMITTER: Pham JW

PROVIDER: S-EPMC443534 | biostudies-literature | 2004

REPOSITORIES: biostudies-literature

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Thermodynamic and structural characterization of 2'-nitrogen-modified RNA duplexes.

Pham John W JW Radhakrishnan Ishwar I Sontheimer Erik J EJ

Nucleic acids research 20040628 11

2'-aminonucleosides are commonly used as sites of post-synthetic chemical modification within nucleic acids. As part of a larger cross-linking strategy, we appended alkyl groups onto the N2' position of 2'-amino-modified RNAs via 2'-ureido and 2'-amido linkages. We have characterized the thermodynamics of 2'-amino, 2'-alkylamido and 2'-alkylureido-modified RNA duplexes and show that 2'-ureido-modified RNAs are significantly more stable than analogous 2'-amido-modified RNAs. Using NMR spectroscop ...[more]

PMID: 15247335

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Project description:Conformational entropy for atomic-level, three dimensional biomolecules is known experimentally to play an important role in protein-ligand discrimination, yet reliable computation of entropy remains a difficult problem. Here we describe the first two accurate and efficient algorithms to compute the conformational entropy for RNA secondary structures, with respect to the Turner energy model, where free energy parameters are determined from UV absorption experiments. An algorithm to compute the derivational entropy for RNA secondary structures had previously been introduced, using stochastic context free grammars (SCFGs). However, the numerical value of derivational entropy depends heavily on the chosen context free grammar and on the training set used to estimate rule probabilities. Using data from the Rfam database, we determine that both of our thermodynamic methods, which agree in numerical value, are substantially faster than the SCFG method. Thermodynamic structural entropy is much smaller than derivational entropy, and the correlation between length-normalized thermodynamic entropy and derivational entropy is moderately weak to poor. In applications, we plot the structural entropy as a function of temperature for known thermoswitches, such as the repression of heat shock gene expression (ROSE) element, we determine that the correlation between hammerhead ribozyme cleavage activity and total free energy is improved by including an additional free energy term arising from conformational entropy, and we plot the structural entropy of windows of the HIV-1 genome. Our software RNAentropy can compute structural entropy for any user-specified temperature, and supports both the Turner'99 and Turner'04 energy parameters. It follows that RNAentropy is state-of-the-art software to compute RNA secondary structure conformational entropy. Source code is available at https://github.com/clotelab/RNAentropy/; a full web server is available at http://bioinformatics.bc.edu/clotelab/RNAentropy, including source code and ancillary programs.

Dataset Information

Thermodynamic and structural characterization of 2'-nitrogen-modified RNA duplexes.

Publications

Thermodynamic and structural characterization of 2'-nitrogen-modified RNA duplexes.

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