Ab initio studies on the H-bonding of hypoxanthine and DNA bases

Paragi, Gábor; Pálinkó, István; Alsenoy, C. van; Gyémánt, I.; Penke, Botond; Tímár, Zoltán

doi:10.1039/b204695d

Cited by 12 publications

(10 citation statements)

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“…There is an especially strong correlation between the HYP:C and G:C dimers, which has been noted from experimental crystal structures of DNA helices. 29,30 As previously reported in the literature, 36 the optimized HYP:G Hoogsteen pair exhibits a large degree of buckle and propeller distortion. Since this distortion will likely not be accommodated within a DNA helix, and experiments suggest only subtle distortions of the local conformation upon incorporation of HYP:G pairs, 34 we have also optimized all hydrogenbonded pairs, as well as nucleobase monomers, in C s Fig.…”

Section: Hydrogen-bonding Interactions Of Hypoxanthinesupporting

confidence: 64%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Rutledge

Wheaton

Wetmore

2007

Phys. Chem. Chem. Phys.

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The hydrogen-bonding and stacking interactions of hypoxanthine, a potential universal nucleobase, were calculated using a variety of methodologies (CCSD(T), MP2, B3LYP, PWB6K, AMBER). All methods predict that the hydrogen-bonding interaction in the hypoxanthine-cytosine pair is approximately 25 kJ mol(-1) stronger than that in the other dimers. Although the calculations support suggestions from experiments that hypoxanthine preferentially binds with cytosine, the trend in the calculated hydrogen-bond strengths for the remaining natural nucleobases do not show a strong correlation with the experimentally predicted binding preferences. However, our calculations suggest that the stacking interactions of hypoxanthine are similar in magnitude to the hydrogen-bonding interactions at all levels of theory (with the exception of B3LYP, which incorrectly predicts stacked dimers to be unstable). Therefore, stacking interactions should also be considered when analyzing the stability of DNA helices containing hypoxanthine and the use of larger models that account for both hydrogen-bonding and stacking within DNA duplexes will likely result in better agreement with experimental observations. For the majority of the dimers, PWB6K and AMBER provide reasonable binding strengths at reduced computational costs, and therefore will be useful techniques for considering larger models.

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Section: Hydrogen-bonding Interactions Of Hypoxanthinesupporting

confidence: 64%

Section: Introductionmentioning

confidence: 99%

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

Rutledge

Wheaton

Wetmore

2007

Phys. Chem. Chem. Phys.

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“…Computational chemistry can individually characterize each discrete interaction in DNA helices and thereby provide a unique approach for understanding the effects of both the hydrogen-bonding and stacking interactions on the overall stability of strands containing universal nucleobases. 11,32,49,50 However, it is not surprising that the calculated stabilities of isolated pairs do not explain the observed discriminatory behavior of hypoxanthine. Indeed, many factors may affect the strength of calculated interactions in hypoxanthinecontaining isolated dimers versus DNA helices.…”

Section: Introductionmentioning

confidence: 98%

“…[52][53][54][55][56][57][58][59][60][61][62] However, duplex melting temperatures indicate that hypoxanthine preferentially binds to cytosine. 2,3,48,63,64 Although the strong preference for cytosine is explained by a greater calculated 49,50 and measured 65 hydrogen-bond strength of the isolated H:C pair compared to pairs involving other natural nucleobases, the trend in the calculated hydrogen-bond strengths between hypoxanthine and the remaining nucleobases (T E A > G) 49 does not match the average trend in the experimental melting temperatures for a range of strand sequences (A > T E G). 2 There is currently no complete explanation for the observed binding preference of hypoxanthine that clarifies the lack of universal binding affinity.…”

Section: Introductionmentioning

confidence: 98%

“…Computational studies have shown that hypoxanthine hydrogen bonds to all natural nucleobases with a significant strength. 49,50 Furthermore, since hypoxanthine differs in structure from guanine by a single amino group, the stacking interactions of isolated hypoxanthine-nucleobase heterodimers calculated at the most accurate levels of theory possible for these systems (CCSD(T)/CBS) are very large. 49 Indeed, computational studies have revealed that H stacks as strongly as it hydrogen bonds to all natural bases except cytosine.…”

Section: Introductionmentioning

confidence: 99%

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A computational proposal for the experimentally observed discriminatory behavior of hypoxanthine, a weak universal nucleobase

Rutledge

Wetmore

2012

Phys. Chem. Chem. Phys.

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A computational model composed of six nucleobases was used to investigate why hypoxanthine does not yield duplexes of equal stability when paired opposite each of the natural DNA nucleobases. The magnitudes of all nearest-neighbor interactions in a DNA helix were calculated, including hydrogen-bonding, intra- and interstrand stacking interactions, as well as 1-3 intrastrand stacking interactions. Although the stacking interactions in DNA relevant arrangements are significant and account for at least one third of the total stabilization energy in our nucleobase complexes, the trends in the magnitude of the stacking interactions cannot explain the relative experimental melting temperatures previously reported in the literature. Furthermore, although the total hydrogen-bonding interactions explain why hypoxanthine preferentially pairs with cytosine, the experimental trend for the remaining nucleobases (A, T, G) is not explained. In fact, the calculated pairing preference of hypoxanthine matches that determined experimentally only when the sum of all types of nearest-neighbor interactions is considered. This finding highlights a strong correlation between the relative magnitude of the total nucleobase-nucleobase interactions and measured melting temperatures for DNA strands containing hypoxanthine despite the potential role of other factors (including hydration, temperature, sugar-phosphate backbone). By considering a large range of sequence combinations, we reveal that the binding preference of hypoxanthine is strongly dependent on the nucleobase sequence, which may explain the varied ability of hypoxanthine to universally bind to the natural bases. As a result, we propose that future work should closely examine the interplay between the dominant nucleobase-nucleobase interactions and the overall strand stability to fully understand how sequence context affects the universal binding properties of modified bases and to aid the design of new molecules with ambiguous pairing properties.

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