Noncanonical Isomers of Nucleoside Cation Radicals: An Ab Initio Study of the Dark Matter of DNA Ionization

Abstract

Cation radicals of DNA nucleosides, 2′-deoxyadenosine, 2′-deoxyguanosine, 2′-deoxycytidine, and 2′-deoxythymidine, can exist in standard canonical forms or as noncanonical isomers in which the charge is introduced by protonation of the nucleobase, whereas the radical predominantly resides in the deoxyribose moiety. Density functional theory as well as correlated ab initio calculations with coupled clusters (CCSD­(T)) that were extrapolated to the complete basis set limit showed that noncanonical nucleoside ion isomers were thermodynamically more stable than their canonical forms in both the gas phase and as water-solvated ions. This indicated the possibility of exothermic conversion of canonical to noncanonical forms. The noncanonical isomers were calculated to have very low adiabatic ion–electron recombination energies (REad) for the lowest-energy isomers 2′-deoxy-(N-3H)­adenos-1′-yl (4.74 eV), 2′-deoxy-(N-7H)­guanos-1′-yl (4.66 eV), 2′-deoxy-(N-3H)­cytid-1′-yl (5.12 eV), and 2′-deoxy-5-methylene-(O-2H)­uridine (5.24 eV). These were substantially lower than the REad value calculated for the canonical 2′-deoxyadenosine, 2′-deoxy guanosine, 2′-deoxy cytidine, and 2′-deoxy thymidine cation radicals, which were 7.82, 7.46, 8.14, and 8.20 eV, respectively, for the lowest-energy ion conformers of each type. Charge and spin distributions in noncovalent cation-radical dA⊂dT and dG⊂dC nucleoside pairs and dAT, dCT, dTC, and dGC dinucleotides were analyzed to elucidate the electronic structure of the cation radicals. Born–Oppenheimer molecular dynamics trajectory calculations of the dinucleotides and nucleoside pairs indicated rapid exothermic proton transfer from noncanonical T+ · to A in both dAT+ · and dA⊂dT+ ·, leading to charge and radical separation. Noncanonical T+ · in dCT+ · and dTC+ · initiated rapid proton transfer to cytosine, whereas the canonical dCT+ · dinucleotide ion retained the cation radical structure without isomerization. No spontaneous proton transfer was found in dGC+ · and dG⊂dC+ · containing canonical neutral and noncanonical ionized deoxycytidine.

Resolution of Identity in Gas-Phase Dissociations of Mono- and Diprotonated DNA Trinucleotide Codons by 15N-Labeling and Computational Structure Analysis

“…Several low-energy B3LYP structures were further reoptimized with M06-2X and the 6-31+G­(d,p) basis set, and the reoptimized geometries were used for single-point energy M06-2X calculations with the 6-311++G­(2d,p) basis set. This level of theory has been shown to give very similar relative nucleoside ion energies compared to those obtained by coupled-clusters calculations with single, double, and disconnected triple excitations (CCSD­(T)) that were expanded to the complete basis set . In addition, our previous studies indicated that dinucleotide , and tetranucleotide ion geometries , that were obtained by M06-2X/6-31+G­(d,p) were consistent with ion structures determined by action spectroscopy measurements.…”

“…Several lowenergy B3LYP structures were further reoptimized with M06-2X 30 theory has been shown to give very similar relative nucleoside ion energies compared to those obtained by coupled-clusters calculations with single, double, and disconnected triple excitations (CCSD(T)) that were expanded to the complete basis set. 31 In addition, our previous studies indicated that dinucleotide 18,32 and tetranucleotide ion geometries 33,34 that were obtained by M06-2X/6-31+G(d,p) were consistent with ion structures determined by action spectroscopy measurements. Solvation energies were addressed with self-consistent reaction field calculations using the polarizable continuum model (PCM) 35 in water dielectric.…”

“…Solvation energies were addressed with self-consistent reaction field calculations using the polarizable continuum model (PCM) in water dielectric. Reference nucleoside proton affinities and gas-phase basicities were calculated using the DFT and CCSD­(T) data reported previously and are summarized in Table S1 (Supporting Information). Rice–Ramsperger–Kassel–Marcus calculations of unimolecular rate constants were performed with the QCPE 644 program of Zhu and Hase that has been modified by expanding the limit for the number of internal degrees of freedom to 1000 and recompiled to run under Windows 7 .…”

The DNA Radical Code. Resolution of Identity in Dissociations of Trinucleotide Codon Cation Radicals in the Gas Phase

“…The reported thermodynamic data refer to 310 K, which is the ion trap ambient temperature. Previous benchmarking of M06-2X/6-311++G­(2d,p) relative energies versus those calculated by coupled cluster methods for nucleobase and nucleoside cation radicals showed a close correlation and identical energy ranking for both sets . Atomic charges and spin densities were obtained from natural population analysis (NPA) calculations with M06-2X/6-311++G­(2d,p).…”

“…Previous benchmarking of M06-2X/6-311++G(2d,p) relative energies versus those calculated by coupled cluster methods for nucleobase and nucleoside cation radicals showed a close correlation and identical energy ranking for both sets. 58 Atomic charges and spin densities were obtained from natural population analysis 59 (NPA) calculations with M06-2X/6-311++G(2d,p). These standard calculations were performed with the Gaussian 16 suite of programs, Revision B.01, licensed from Gaussian, Inc. (Wallingford, CT).…”