A Combined Computational and Experimental Study of the Hydrogen-Bonded Dimers of Xanthine and Hypoxanthine

Abstract

In addition to uracil, the noncanonical nucleobases xanthine and hypoxanthine are important lesions that are formed from the canonical bases when a cell is under oxidative stress. It is known that they lead to point mutations; however, more detailed information about their ability to form hydrogen-bonded complexes is not available. In the present paper such information is obtained by a combined experimental and theoretical approach. Accurate association constants of xanthosine and inosine dimers are determined by concentration dependent 1H NMR experiments, and a structural characterization of individual complexes formed in solution is performed through measurements under slow exchange conditions at very low temperatures. An interpretation of the experimental data concerning complex geometries becomes possible through a comparison of measured and computed NMR chemical shifts. Further qualitative insights into the hydrogen bonding abilities of xanthine and hypoxanthine are obtained by a theoretical characterization of all possible pairing modes of xanthine and hypoxanthine dimers and by a comparison with simplified model systems. The influence of a polar medium on the bonding properties is also estimated and the importance of the various effects is discussed. Our analysis shows to what extent secondary electronic and electrostatic effects influence the hydrogen bonding properties of xanthine and hypoxanthine in the gas phase and in polar solvents.

How Can Rotaxanes Be Modified by Varying Functional Groups at the Axle?—A Combined Theoretical and Experimental Analysis of Thermochemistry and Electronic Effects

“…[61] Previous computational studies employed an approach suggested by Williams et al, which considers the transition to the fluid as a two-step process by first condensing the gaseous compound to a pure liquid and subsequently diluting the pure liquid to the 1 m standard state. [62][63][64] This procedure should, in principle, give more accurate results concerning entropy changes in solution and comparison with experimental data, but we refrain from using this approach because our aim is to predict entropy changes from pure theory. The method of Williams et al requires knowledge of macroscopic quantities, for example, the condensation entropy, that are not available in the single-molecule picture.…”

“…This means that even in calculations employing continuum solvation models such as COSMO, the translational and rotational entropy contributions for the gas phase are employed, which do not accurately reflect the conditions in the condensed phase due to solvent–solute interactions and a clearly reduced free volume of translation in the fluid 61. Previous computational studies employed an approach suggested by Williams et al., which considers the transition to the fluid as a two‐step process by first condensing the gaseous compound to a pure liquid and subsequently diluting the pure liquid to the 1 M standard state 62–64. This procedure should, in principle, give more accurate results concerning entropy changes in solution and comparison with experimental data, but we refrain from using this approach because our aim is to predict entropy changes from pure theory.…”

Acidity and basicity interplay in amide and imide self-association

“…The formation of amide and imide dimers is frequently studied by NMR or IR spectroscopy to determine self-association constants in solution. 7 , 8 Rebek and co-workers 9 examined the intramolecular imide–imide and amide–amide association through NMR measurements. The corresponding results indicate that despite their lower acidity, amides exhibit stronger self-associations than imides.…”

A computational characterization of the hydrogen-bonding and stacking interactions of hypoxanthine

“…Computational chemistry can play an important role in understanding the binding interactions between HYP and the natural nucleobases since information about discrete interactions can be more readily obtained compared with experiment. Indeed, computational studies of the hydrogen-bonding ability, 36,37 as well as other molecular properties, [38][39][40][41][42][43][44][45] of hypoxanthine have recently appeared in the literature. However, information about stacking interactions involving hypoxanthine has yet to be obtained.…”