The Physical Basis of Nucleic Acid Base Stacking in Water

Abstract

It has been argued that the stacking of adenyl groups in water must be driven primarily by electrostatic interactions, based upon NMR data showing stacking for two adenyl groups joined by a 3-atom linker but not for two naphthyl groups joined by the same linker. In contrast, theoretical work has suggested that adenine stacking is driven primarily by nonelectrostatic forces, and that electrostatic interactions actually produce a net repulsion between adenines stacking in water. The present study provides evidence that the experimental data for the 3-atom-linked bis-adenyl and bis-naphthyl compounds are consistent with the theory indicating that nonelectrostatic interactions drive adenine stacking. First, a theoretical conformational analysis is found to reproduce the observed ranking of the stacking tendencies of the compounds studied experimentally. A geometric analysis identifies two possible reasons, other than stronger electrostatic interactions, why the 3-atom-linked bis-adenyl compounds should stack more than the bis-naphthyl compounds. First, stacked naphthyl groups tend to lie further apart than stacked adenyl groups, based upon both quantum calculations and crystal structures. This may prevent the bis-naphthyl compound from stacking as extensively as the bis-adenyl compound. Second, geometric analysis shows that more stacked conformations are sterically accessible to the bis-adenyl compound than to the bis-naphthyl compound because the linker is attached to the sides of the adenyl groups, but to the ends of the naphthyl groups. Finally, ab initio quantum mechanics calculations and energy decompositions for relevant conformations of adenine and naphthalene dimers support the view that stacking in these compounds is driven primarily by nonelectrostatic interactions. The present analysis illustrates the importance of considering all aspects of a molecular system when interpreting experimental data, and the value of computer models as an adjunct to chemical intuition.

Formamide and the origin of life

“…Energetically favorable stacking interactions between bases play an important role in determining and stabilizing nucleic acid structures [117,118]. The physical fundamentals of nucleic acid bases stacking in water have been accurately defined and reviewed [119][120][121], the thermodynamic parameters for stacking have been determined [122,123].…”

Borate Minerals and RNA Stability

“…The stability of RNA phosphodiester bonds has repeatedly been associated with the stacking interactions between adjacent bases [21][22][23]. Nucleic acid base-stacking is at present an understood phenomenon [24][25][26][27][28]. The possibility that the initial stability of the PolyA oligonucleotide towards hydrolysis is a base stacking-related effect was discussed in [15].…”

A systematically coarse-grained model for DNA and its predictions for persistence length, stacking, twist, and chirality

“…Sterically, bases of DNA more accurately resemble a flat plate than a spherical object. Energetically, base stacking interactions, predominantly governed by electron correlation (van der Waals) interactions 24 , play a significant if not dominant role in the stability of the double helix 25 . We adopt a systematic coarse-graining approach, where we parameterize the effective interactions through all-atom simulations wherever possible.…”