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. 2009 Dec 16;131(49):17759-61.
doi: 10.1021/ja905795v.

Urea destabilizes RNA by forming stacking interactions and multiple hydrogen bonds with nucleic acid bases

U Deva Priyakumar  1 , Changbong Hyeon, D Thirumalai, Alexander D Mackerell Jr
Affiliations

Urea destabilizes RNA by forming stacking interactions and multiple hydrogen bonds with nucleic acid bases

U Deva Priyakumar et al. J Am Chem Soc. .

Abstract

Urea titration of RNA by urea is an effective approach to investigate the forces stabilizing this biologically important molecule. We used all atom molecular dynamics simulations using two urea force fields and two RNA constructs to elucidate in atomic detail the destabilization mechanism of folded RNA in aqueous urea solutions. Urea denatures RNA by forming multiple hydrogen bonds with the RNA bases and has little influence on the phosphodiester backbone. Most significantly we discovered that urea engages in stacking interactions with the bases. We also estimate, for the first time, the m-value for RNA, which is a measure of the strength of urea-RNA interactions. Our work provides a conceptual understanding of the mechanism by which urea enhances RNA folding rates.

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Figures

Figure 1
Figure 1
Effect of urea on the P5GA hairpin. A. Secondary structure map of P5GA. B. Probability distribution of the N1–N3, N1–N1 and N1–O2 inter-atomic distances of the GC(AU), GA and GU base pairs, respectively, in the stem. The dotted line is the integrated probability over the distances.
Figure 2
Figure 2
Probability distributions of the dihedral angles along phosphodiester backbone of the RNA hairpin at [C]=0, 6, 8 M.
Figure 3
Figure 3
A. RDFs of OU around the RNA nitrogen atoms at 6M and 8M urea. The water RDFs are scaled by 5 and 10 for the urea oxygen plots. Results are shown for the RNA backbone atoms (phosphodiester and sugar oxygen) and RNA bases. B. Structure with multiple hydrogen bonds between urea and RNA base and phosphate group. The panels on the right show the structure of urea-base stacking and the corresponding RDFs between the urea carbon and C4, C5, C2 (A and G) and C5, C6 (C and U) atoms. The contributions from individual atom are in SI Fig.13.
Figure 4
Figure 4
Urea-induced structural transitions. A. The structure of RNA duplex (left). Inverse N1–N3 distances of the four base pairs (color-code, blue, green, red and black are used consistently) as a function of time at [C] = 0M (top) and [C[ = 6M (bottom); B. Fraction of bound fB and change in free energy ΔG as a function of urea concentrations. The fit is made for m-value analysis; C. RDFs of urea oxygen and water oxygen with respect to H1 atom of the G base when the duplex is bound or denatured at [C]=6 M.
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