Abstract

SEQUENCE-DEPENDENT THERMODYNAMIC STABILITY AND QUANTUM-CHEMICAL REACTIVITY DESCRIPTORS OF ADENINEINITIATED DNA TRINUCLEOTIDES: A SEMI-EMPIRICAL AM1/MOPAC 2016 INVESTIGATION

*Bojja Rajeshwar Rao

Abstract

The sequence-dependent electronic structure of DNA oligomers underlies key biological phenomena, including oxidative lesion formation, radical whole transport, and mutational hot-spot behaviour. In this work, the complete set of sixteen adenineinitiated DNA trinucleotides (5′-A-N2-N3-3′; N2, N3 ∈ {A, C, G, T}) was investigated using the semi-empirical AM1 Hamiltonian implemented in MOPAC2016 (Version 23.2.5W), with implicit aqueous solvation described by the Conductorlike Screening Model (COSMO). Fully optimized geometries were used to extract heats of formation (ΔHf), dipole moments, frontier molecular orbital (EHOMO/ELUMO) energies, COSMO solvent-accessible surface areas and volumes, and molecular weights. Koopmans'-theorem-derived conceptual density functional theory descriptors — ionization potential, electron affinity, electronegativity, chemical hardness, softness, chemical potential, and the global electrophilicity index (ω) — were subsequently computed for every sequence. The most thermodynamically stable trinucleotide was ATT (ΔHf = −949.31 kcal mol⁻¹), whereas AGG was the least stable (ΔHf = −660.31 kcal mol⁻¹). Dipole moments spanned a sixteen-fold range (1.55–18.08 D), with the purine-rich AGC sequence showing the largest polarity. The HOMO–LUMO gap varied from 7.82 eV (ACG) to 8.60 eV (ATA), and, as required by their shared definition, tracked the chemical hardness with a Pearson correlation coefficient of r = 1.00. The pyrimidine-terminated ACT sequence displayed the highest electrophilicity index (ω = 2.593 eV), identifying it as the most electrophilic member of the series, while AAC was the least electrophilic (ω = 2.334 eV). Thermodynamic stability (ΔHf) and electronic reactivity indices were only weakly correlated (|r| < 0.3), indicating that sequence-dependent thermodynamic and frontier-orbital reactivity behave as largely independent structural descriptors. These results provide a systematic, internally consistent quantum-chemical reference set for adenine-initiated trinucleotide fragments and offer mechanistic groundwork for rationalizing sequence-specific DNA reactivity, oxidative susceptibility, and future ligand/mutagen-interaction studies.

Keywords: DNA trinucleotides, adenine, AM1 semi-empirical method, MOPAC2016, COSMO solvation, HOMO–LUMO gap, conceptual DFT, electrophilicity index.