UV photoelectron and ab initio quantum mechanical characterization of valence electrons in Na(+)-water-2'-deoxyguanosine 5'-phosphate clusters: electronic influences on DNA alkylation by methylating and ethylating carcinogens.

Abstract

UV photoelectron data for 1,9-dImethylguanine, 3-hydroxytetrahydrofuran, and water, and results from ab initio self-consistent field (SCF) and post-SCF molecular orbital calculations were employed to describe valence electrons in clusters of 2'-deoxyguanosine 5'-phosphate (5'-dGMP-) with four water molecules and a phosphate-bound sodium ion. Two clusters (A and B) were ex . In A, Na+ is coordinated to 5'-dGMP-. In B, Na+ and 5'-dGMP-are separated by water. In 5'-dGMP-clusters, the nucleotide valence ionization potentials (IPs) are different from those previously reported for isolated 5'-dGMP-. The smIllest IP in isolated 5'-dGMP-(4.6 eV) arises from the phosphate group; thesmallestIPs inA (8.2 eV) andB (7.9 eV) arise from the base. In the clusters, the IPs associated with the seven upper occupied base orbitals differ from corresponding IPs in 1,9-dimethylguanine by less than 0.4 eV. In A and B, the smaller ]IP of the base, compared with the phosphate group, is consistent with reactivity data indicating that DNA and RNA are subject to electrophilic SN2 attack by carcinogens such as N-methyl-Nnitrosourea, dimethyl and diethyl sulfate, and methyl and ethyl methanesulfonate, in which more than 75% of nucleotide alkylation occurs at the bases. While isolated nucleotides (1, 2, 4) have been investigated, nucleotides in the presence of water and counterions, which interact with DNA in physiological environments, have not. One goal of this investigation is to examine electrons in 2'-deoxyguanosine 5'-phosphate (5'-dGMP-) with 4 water molecules and a Na+ counterion. DNA binding occurs dynamically on a picosecond time scale (5, 6); nevertheless, information about solvent-counterion influences on nucleotide electronic structure can be obtained by examining statistically significant clusters. Fig. 1 shows two clusters (A and B) in which Na+ and 3 of the 4 water molecules bind to the phosphate group of 5'-dGMP-.X-ray (7,8), IR (9), and NMR (10) data indicate that phosphate in DNA is a principal hydration and Na+ binding site. In crystals of guanylyl (3'-5')cytidine nonahydrate, Na+ ions are octahedrally coordinated to the negative 0 atoms of phosphate and to H20 (11). Different theoretical approaches (5,(12)(13)(14)(15) indicate that Na+ binds in the grooves of DNA and along the backbone; however, recent molecular dynamics calculations point to the importance of Na+ binding at

An Active Site Aromatic Triad in Escherichia coli DNA Pol IV Coordinates Cell Survival and Mutagenesis in Different DNA Damaging Agents

“…These polymerases likely bypass 3-methyladenine (3-meA; [1], [19], [20], [21], [33], [34]), a prevalent alkylation lesion that persists on the DNA and brings about replication fork stalling and cell death [20], [21], [35], [36]. Indeed, E. coli strains lacking the dinB gene ( ΔdinB ) are sensitive to several alkylating agents, such as methyl methanesulfonate (MMS; [19]).…”

“…It is known that base excision repair pathways are the primary cellular response to alkylation damage [1] , [28] , [29] , [30] , [31] , [32] , though Y family DNA polymerases are also part of this response [1] , [19] , [20] , [21] . These polymerases likely bypass 3-methyladenine (3-meA; [1] , [19] , [20] , [21] , [33] , [34] ), a prevalent alkylation lesion that persists on the DNA and brings about replication fork stalling and cell death [20] , [21] , [35] , [36] . Indeed, E. coli strains lacking the dinB gene ( ΔdinB ) are sensitive to several alkylating agents, such as methyl methanesulfonate (MMS; [19] ).…”

Aqueous Ionization and Electron-Donating Properties of Dinucleotides: Sequence-Specific Electronic Effects on DNA Alkylation

“…Earlier investigations of mononucleotide ionization potentials 1,2,10-13,15 indicated that at the SCF level the upper occupied orbitals are largely localized on either the base, sugar, or phosphate groups. The combined theoretical and experimental method employed in evaluating nucleotide gas-phase IPs exploited this finding and the observation that SCF calculations describe differences in IPs caused by changes in structure more accurately than they provide absolute values of ionization energies. ,,, To examine the energetics of DNA ionization in the most useful way, it is important to recognize that in physiological surroundings DNA interacts with water, counterions, and protein. , Interactions with water and small counterions, like Na + , generally occur dynamically 18 on a time scale of pico- to nanoseconds. 18a,b, Results from investigations of isolated nucleotide−water−counterion clusters, in fixed geometries based on crystallographic data and in geometries that molecular dynamics calculations indicate are statistically significant, demonstrate that counterion electrostatic interactions significantly increase nucleotide IPs. ,,, For example, the lowest energy base IP in the isolated gas-phase nucleotide, 5‘-dGMP - , is approximately 1.8 eV smaller than that of 5‘-dGMP - in a gas-phase cluster in which the phosphate group interacts with an Na + ion through a single H 2 O solvation shell …”

A Review of the Role of the Sequence-Dependent Electrostatic Landscape in DNA Alkylation Patterns

“…Klopman et al attempted, with limited success, to relate the alkylation patterns to effects of base stacking on reaction potentials (42). Another approach to the question was proposed by LeBreton who tried to relate reactivity at different G's to an increase in p polarizability in the highest HOMO of G that reduces the transition state activation involving charge transfer (43)(44)(45). It was calculated that the ionization potential of G, which has the lowest ionization potential of the nucleobases, is decreased when it is in the interior of a hyper-reactive G 3-4 stretch.…”