The present work characterizes the gas-phase stacking interactions between four aromatic amino acid residues (histidine, phenylalanine, tyrosine, and tryptophan) and adenine or 3-methyladenine due to the proposed utilization of these interactions by enzymes that repair DNA alkylation damage. The MP2 potential energy surfaces of the stacked dimers are considered as a function of four variables (vertical displacement, angle of rotation, horizontal displacement, and tilt angle) using a variety of basis sets. It is found that the maximum stacking interaction energy decreases with the amino acid according to TRP > TYR approximately HIS > PHE for both nucleobases. However, the magnitude of the stacking interaction significantly increases upon alkylation (by 50-115%). Comparison of the stacking energies calculated using our surface scans to those estimated from experimental crystal structures indicates that the stacking interactions within the active site of 3-methyladenine DNA glycosylase can account for 65-75% of the maximum possible stacking interaction between the relevant molecules. The decrease in stacking in the crystal structure arises due to significant differences in the relative orientations of the nucleobase and amino acid. Nevertheless, alkylation is found to significantly increase the stacking energy when the crystal structure geometries are considered. Our calculations provide computational support for suggestions that alkylation enhances the stacking interactions within the active site of DNA repair enzymes, and they give a measure of the magnitude of this enhancement. Our results suggest that alkylation likely plays a more important role in substrate identification and removal than the nature of the aromatic amino acid that interacts with the substrate via stacking interactions.

The slight variations among the proton affinities and bond strengths of the C-C bonds in straight-chain n-alkanes have been determined to 1 kcal mol -1 accuracy for the first time, using computational quantum chemistry. Four computational methods (B3LYP, MP2, CCSD(T), and G2) were used to study n-alkanes (up to C 20 H 42 with B3LYP), including computations on the related alkyl radicals, carbenium ions, and carbonium ions. The proton affinities of the C-C bonds vary from 142 to over 166 kcal mol -1 , are highest for the center C-C bond, and decrease monotonically toward the end bonds. Bond strength, unlike proton affinity, is very constant (88 kcal mol -1 ), except for the R and bonds (89 and 87 kcal mol -1 , respectively). For thermal cracking, the results suggest that the most favored initiation step is the breaking of the bond of the alkane to create an ethyl radical. For Bronsted-acid-catalyzed cracking of straight-chain paraffins, if the initiation mechanism is via carbonium ions, then the results indicate that the central C-C bonds of n-alkanes will be most attractive to the Bronsted proton. However, for direct protolysis (Bronsted-mediated fission) of an n-alkane via a carbonium intermediate, the net exothermicities do not strongly discern among the C-C bonds. Trends in molecular geometry and infrared spectra features are also presented, and a signature IR band is predicted for carbonium ions that should aid in their identification.

The present study uses density functional theory to investigate the effects of hydrogen bonding on the acidity of C5-and C6-substituted uracil derivatives. The proton affinities and acidities of uracil donor and acceptor sites generally decrease and increase, respectively, with an increase in the electronegativity of the uracil substituent. Despite these substituent effects, the binding strengths of small molecules (NH 3 , H 2 O, or HF) to the uracil derivatives are relatively independent of the substituent, which indicates that the changes in the uracil proton affinity and acidity effectively cancel. The acidities of substituted uracil complexes increase not only with the electronegativity of the substituent, but also with the acidity of the small molecule bound to the uracil ring. However, the magnitude of the effect of hydrogen bonding on the acidity of uracil derivatives is not dependent on the nature or position of the substituent. Our results lead to a greater fundamental understanding of the effects of substituents on the hydrogen-bonding properties of uracil, which may have implications for understanding biological applications and processes that involve these modified nucleobases.

Complexes between ammonia, water, or hydrogen fluoride and adenine, guanine, or their 8-oxo derivatives are investigated using density-functional theory. The binding strengths of the neutral and (N9) anionic complexes are considered for a variety of purine binding sites. The effects of hydrogen-bonding interactions on the (N9) acidity of the purine derivatives are considered as a function of the molecule bound and the binding site. It is found that hydrogen-bonding interactions with one molecule can increase the acidity of purine derivatives by up to 60 kJ mol(-1). The (calculated) simultaneous effects of up to four molecules on the acidity of the purine derivatives are also considered. Our data suggest that the effects of more than one molecule on the acidity of the purines are generally less than the sum of the individual (additive) effects, where the magnitude of the deviation from additivity increases with the number, as well as the acidity, of molecules bound. Nevertheless, the increase in the acidity due to additional hydrogen-bonding interactions is significant, where the effect of two, three, or four hydrogen-bonding interactions can be as large as approximately 95, 115, and 130 kJ mol(-1), respectively. The present study provides a greater fundamental understanding of hydrogen-bonding interactions involving the natural purines, as well as those generated through oxidative DNA damage, which may aid the understanding of important biological processes.