Abstract
Understanding the structure-function relationships of RNA has become increasingly important given the realization of its functional role in various cellular processes. Chemical denaturation of RNA by urea has been shown to be beneficial in investigating RNA stability and folding. Elucidation of the mechanism of unfolding of RNA by urea is important for understanding the folding pathways. In addition to studying denaturation of RNA in aqueous urea, it is important to understand the nature and strength of interactions of the building blocks of RNA. In this study, a systematic examination of the structural features and energetic factors involving interactions between nucleobases and urea is presented. Results from molecular dynamics (MD) simulations on each of the five DNA/RNA bases in water and eight different concentrations of aqueous urea, and free energy calculations using the thermodynamic integration method are presented. The interaction energies between all the nucleobases with the solvent environment and the transfer free energies become more favorable with respect to increase in the concentration of urea. Preferential interactions of urea versus water molecules with all model systems determined using Kirkwood-Buff integrals and two-domain models indicate preference of urea by nucleobases in comparison to water. The modes of interaction between urea and the nucleobases were analyzed in detail. In addition to the previously identified hydrogen bonding and stacking interactions between urea and nucleobases that stabilize the unfolded states of RNA in aqueous solution, NH-π interactions are proposed to be important. Dynamic properties of each of these three modes of interactions have been presented. The study provides fundamental insights into the nature of interaction of urea molecules with nucleobases and how it disrupts nucleic acids.
Highlights
Www.nature.com/scientificreports significant changes in nucleic acid structures by interacting with the exposed surface of nucleobases, which subsequently results in the destabilization of nucleic acids[27,28,29]
The interaction energies presented do not include the entropic contributions and thermodynamic integration free energy calculations were performed details of which are presented
Favorable dispersion interactions result into large values of mean time distribution for purines compared to pyrimidines
Summary
Www.nature.com/scientificreports significant changes in nucleic acid structures by interacting with the exposed surface of nucleobases, which subsequently results in the destabilization of nucleic acids[27,28,29]. Urea has been shown to preferentially solvate the nucleobases and helps in the denaturation process of nucleic acids while nucleic acid backbone has no major role in the denaturation process[28] This implies urea-nucleobase interactions are crucial in understanding the mechanism by which the unfolded RNA is stabilized in the presence of urea than in the absence. Presence of stacking and hydrogen bonding interactions between urea and nucleobases contribute to the destabilization of nucleic acid structures[28,29,33,34,35,36]. This study is performed for an improved understanding of the effect of aqueous urea at individual base level (purines and pyrimidines) which helps to rationalize the contribution of these nucleobases towards stabilizing the unfolded state in the presence of urea. Analyses from our simulations have allowed us to answer several questions: How urea forms stable interactions with nucleobases? How nucleobases preferentially interacts with urea than pure water? What are the solvation free energy changes involved in the interactions and which are the prominent interactions favored by urea while interacting with these nucleobases? This study explains the strength and nature of urea-nucleobase interactions and gives detailed insights to discern the mechanism of urea-induced nucleic acid disruption
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