Characterization of Nucleobase−Amino Acid Stacking Interactions Utilized by a DNA Repair Enzyme

Abstract

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.

Comparison of Intrinsic Stacking Energies of Ten Unique Dinucleotide Steps in A-RNA and B-DNA Duplexes. Can We Determine Correct Order of Stability by Quantum-Chemical Calculations?

“…The d-polarization functions are capable of filling the gap between the interacting monomers, which significantly improves the description of base stacking interactions compared with the standard 6-31G* basis set. The MP2/6-31G*(0.25) method has been the most widely used ab initio technique to study aromatic stacking in the past literature 31,35,50,51,60,85,100,101,[107][108][109][110][111][112][113][114][115][116][117][118][119][120] and has only recently been replaced by CBS(T). The MP2/6-31G*(0.25) method is entirely sufficient to capture the nature of base stacking, and therefore all conclusions reported with this method remain qualitatively valid.…”

Investigation of the effect of π–π stacking interaction on the properties of –CONH2 functional group of benzamide

“…They have been displayed in drug-enzyme bindings [6], protein folding [7], and the crystal packing of organic molecules [3,8,9].…”

Simultaneous interactions of pyridine with substituted benzene ring and H–F in X-ben⊥pyr···H–F complexes: a cooperative study

“…These interactions control the three-dimensional structures of biological macromolecules such as DNA, RNA, and protein. In addition, the knowledge of weak molecular interactions is virtually essential for the design and synthesis of molecules that adopt predefined conformations [26][27][28][29][30][31][32][33][34]. Despite the great importance of these molecular systems from a biological point of view, relatively little attention has been devoted to the discussion of the nature of these interactions.…”

“…Despite the great importance of these molecular systems from a biological point of view, relatively little attention has been devoted to the discussion of the nature of these interactions. An understanding of their strength and orientational preference has been challenging problem experimentally and theoretically [28][29][30][31].…”

“…It is worth mentioning that recent studies have shown that (1) the favorable nature of stacked conformations in protein environment must not be related with the higher accessibility of hydrogen bond forming groups [40] and (2) the stacking on itself does not have an overall strengthening on hydrogen bond in DNA [41][42][43]. Although a lot of papers have widely been published on stacking interactions, the cooperative effect of stacking and hydrogen bond has given less attention [7,12,15,20,29,30]. Very interesting cooperativity effects are present in complexes where hydrogen bond and stacking interactions coexist.…”