Urea Destabilization of DNA and RNA Double Helices: Preferential Interactions with Nucleobase Conjugated Pi-Pi-Systems

Abstract

Thermal denaturation transition temperatures of AT (adenine-thymine)- and AU (adenine-uracil)-rich double helices decrease to a greater extent in aqueous urea solutions than GC (guanine-cytosine)-rich double helices. The work presented here seeks to identify the chemical functional groups urea preferentially interacts with to account for the greater destabilization of AT- and AU-rich double helices. Vapor pressure osmometry was used to determine the preferential interaction coefficients of urea with nucleoside 5′-monophosphates (5′-NMPs) to quantify the accumulation of urea near the 5′-NMP solvent accessible surface areas. Additionally, molecular dynamics (MD) simulations of the 5′-NMPs in explicit water and 1 molal urea predict urea preferential interactions above and below the nucleobase plane through pi-pi interactions. These MD simulation results are supported by the strong correlation between the fraction of accessible surface area devoted to the base conjugated pi-system and the preferential interaction coefficients determined from vapor pressure osmometry. Implications for urea destabilization of DNA and RNA double helices are discussed.