Abstract

THERMODYNAMIC STABILITY AND FRONTIER MOLECULAR ORBITAL–DERIVED REACTIVITY DESCRIPTORS OF THYMINEINITIATED DNA TRINUCLEOTIDES: A SEMI-EMPIRICAL AM1 (MOPAC2016) STUDY

Dr. Bojja Rajeshwar Rao*

Abstract

DNA trinucleotide fragments contribute to local sequencedependent stability, charge-transfer behaviour, and susceptibility to oxidative damage, yet the electronic-structure basis of these differences at the trinucleotide level remains incompletely characterized. In this study, all sixteen 5′- Thymine-initiated DNA trinucleotides (5′-T–R–R-3′; R = A, C, G, T) were geometry-optimized using the Austin Model 1 (AM1) semi-empirical Hamiltonian implemented in MOPAC2016 (v23.2.5W). Heats of formation (ΔHf), dipole moments, frontier molecular orbital (EHOMO/ELUMO) energies, COSMO solvent-accessible surface areas and volumes, and conceptual density-functional-theory global reactivity descriptors—including ionization potential, electron affinity, electronegativity, chemical hardness, softness, chemical potential, and electrophilicity index (ω)—were calculated and systematically compared among the sequences. TTT exhibited the most negative heat of formation (ΔHf = −1097.55 kcal mol⁻¹), whereas TAA showed the least negative value (−801.38 kcal mol⁻¹). Overall, sequences containing predominantly pyrimidine bases displayed more negative heats of formation than sequences enriched in purine bases. The HOMO–LUMO energy gap (ΔE) ranged from 7.80 eV for TGG to 9.42 eV for TCA. As expected from their definitions, ΔE showed an almost perfect positive correlation with chemical hardness (r ≈ 1.00) and strong negative correlations with softness (r = −0.996) and electrophilicity (r = −0.953 for the LUMO-based relationship). The TGG and TGA trinucleotides, characterized by a 5′-GG motif, exhibited relatively small HOMO–LUMO gaps, high dipole moments, and high electrophilicity indices, indicating enhanced electronic softness and susceptibility to electron-transfer processes. These findings are consistent with the established role of guanine-rich DNA sequences as important sites for oxidative charge transfer and damage. The sequence-resolved thermodynamic, structural, and electronic descriptors obtained here provide a compact reference dataset for understanding sequence-dependent DNA reactivity and for developing structure–property relationships relevant to oxidative DNA damage, nucleic-acid-based drug design, and biosensor applications.

Keywords: AM1 semi-empirical method, MOPAC2016, DNA trinucleotides, HOMO–LUMO gap, heat of formation, conceptual density functional theory, electrophilicity index, COSMO.