The solvation, partitioning, hydrogen bonding, and dimerization of nucleotide bases: a multifaceted challenge for quantum chemistry

Abstract

We present M06-2X density functional calculations of the chloroform/water partition coefficients of cytosine, thymine, uracil, adenine, and guanine and calculations of the free energies of association of selected unsubstituted and alkylated nucleotide base pairs in chloroform and water. Both hydrogen bonding and π-π stacking interactions are considered. Solvation effects are treated using the continuum solvent models SM8, SM8AD, and SMD, including geometry optimization in solution. Comparison of theoretical results with available experimental data indicates that all three of these solvation models predict the chloroform-water partition coefficients for the studied nucleobases qualitatively well, with mean unsigned errors in the range of 0.4-1.3 log units. All three models correctly predict the preference for hydrogen bonding over stacking for nucleobase pairs solvated in chloroform, and SM8, SM8AD, and SMD show similar accuracy in predicting the corresponding free energies of association. The agreement between theory and experiment for the association free energies of the dimers in water is more difficult to assess, as the relevant experimental data are indirect. Theory predicts that the stacking interaction of nucleobases in water is more favorable than hydrogen bonding for only two out of three tested hetero-dimers.

Computational study of the thermodynamic stabilities of hydrogen-bonded complexes in solution

“…It is noted that the calculated binding free energy of −8.8 kcal/ mol for the 30-29 pair (methylated CG) in chloroform is in reasonable agreement with the upper limit of the experimental value of −6.8 kcal/mol. Moreover, the binding energies (ΔE) for AT pair and CG pair from cc-pVDZ and 6-31G(d,p) basis sets agree very well with the value of −32.06 kcal/mol from higher-order quantum calculations at the CCSD(T) level [25]. Apparently, the cc-pVDZ basis Table 1 Calculated gas-and solution-phase (CHCl 3 ) binding energies (kcal/mol) for nucleobase pairs and alkylated AT pairs at M06-2X and SMD/cc-pVDZ level of theory, and previous results with the 6-31G** and 6-31+G** basis sets a Ref.…”

“…These uncorrected results were also compared favorable to the calculations by Cramer, Truhlar and coworkers of which the frequencies were scaled, and all frequencies below 50 cm −1 were raised to 50 cm −1 to account for inadequate harmonic vibration approximations [25]. The M06-2X calculations of both Cramer and Truhlar et al and ours did not include basis set superposition error (BSSE) corrections as did with the original M06-2X model development.…”

“…Apparently, the cc-pVDZ basis Table 1 Calculated gas-and solution-phase (CHCl 3 ) binding energies (kcal/mol) for nucleobase pairs and alkylated AT pairs at M06-2X and SMD/cc-pVDZ level of theory, and previous results with the 6-31G** and 6-31+G** basis sets a Ref. [25] b Refs. [31,34] c AT1 refers to 9-HexA-1-HexT, WC (see Figure S1) d AT2 refers to 9-HexA-1-HexT, RWC e AT3 refers to 9-HexA-1-HexT, H f AT4 refers to 9-HexA-1-HexT, RH g Ref.…”

“…To validate our computational methods with the gas-phase optimizations at M06-2X/cc-pVDZ level of theory, and solution-phase optimizations at SMD/M06-2X/cc-pVDZ level, we first calculated the free energies of association for the nucleobase pairs of AT, AU, CG and four long alkylated AT pairs of 9-hexyladenine and 1-hexylthymine in chloroform solvent [25]. Table 1 lists our computed results along with those from the two methods by Cramer, Truhlar et al and the experimental values which were summarized in recent publications [31,34].…”

“…Leszczynski and coworkers have made efforts to accurately predict thermodynamic parameters for intermolecular complexes including adsorption of polycyclic aromatic hydrocarbons and nitroaromatic compounds with carbon surfaces in water by using Minnesota density functionals, M05-2X and M06-2X with 6-31+G(d,p), cc-pVDZ, and cc-pVTZ basis sets and the PCM model with scalings [21][22][23][24]. Cramer, Truhlar and coworkers carried out a comprehensive computational study of natural and substituted H-bonded nucleobase dimers formed by adenine (A), thymine (T), guanine (G), cytosine (C), and uracil (U) in the gas phase, chloroform and water solution [25]. They calculated the free energies of association of 18 H-bonded base pairs using the M06-2X and three Minnesota solvation models, SM8, SM8AD and SMD with the 6-31G(d,p) and 6-31+G(d,p) basis sets [26][27][28][29][30].…”