Abstract

COMPUTATIONAL STUDY OF THERMODYNAMIC STABILITY AND FRONTIER-ORBITAL-BASED REACTIVITY DESCRIPTORS OF GUANINE-INITIATED DNA TRINUCLEOTIDES: AN AM1/MOPAC2016 INVESTIGATION

Dr. Bojja Rajeshwar Rao*

ABSTRACT

Guanine (G) is the most readily oxidised of the four canonical DNA bases and represents a major site for hole trapping following one-electron oxidation of DNA. Sequence-dependent electronic interactions can therefore influence the localisation and reactivity of oxidative charge in guanine-containing DNA. In this study, the complete set of sixteen guanine-initiated DNA trinucleotides (5′-G–N–N-3′; N = A, C, G, T) was investigated using the semi-empirical Austin Model 1 (AM1) Hamiltonian as implemented in MOPAC2016 (version 23.2.5w). All structures were fully geometry-optimised, and heats of formation (ΔHf), dipole moments, COSMO surface areas and volumes, and frontier molecular orbital (HOMO/LUMO) energies were obtained. Conceptual-DFT global reactivity descriptors, including ionisation potential (IP), electron affinity (EA), electronegativity (χ), chemical potential (μ), global hardness (η), global softness (S), and Parr electrophilicity (ω), were derived from the frontier orbital energies using Koopmans-theorem approximations. GTT was identified as the thermodynamically most stable trinucleotide (ΔHf = −993.38 kcal mol−1), whereas GAA was the least stable (−696.75 kcal mol−1), giving a variation of nearly 300 kcal mol−1. The moderate correlation between ΔHf and molecular weight (r = 0.50, p = 0.05) indicates that molecular size alone does not account for the substantial sequence dependence of thermodynamic stability, which is consistent with additional contributions from sequence-dependent base stacking and electronic interactions. The HOMO energies varied within a relatively narrow 0.41 eV range (−8.396 to −8.805 eV), consistent with the dominant electronic contribution of the 5′-terminal guanine to the highest occupied molecular orbital and its established role as a primary hole-trapping site in DNA. GTG exhibited the largest electrophilicity index (ω = 2.935 eV) and dipole moment (15.62 D), whereas GGC showed the lowest electrophilicity (ω = 2.488 eV). Global hardness and softness were almost perfectly inversely correlated (r = −0.998), while electronegativity and chemical potential showed the expected exact inverse relationship (r = −1.000) arising from their definitions. Overall, the results demonstrate pronounced sequence-dependent variation in the thermodynamic and electronic properties of guanine-initiated DNA trinucleotides and provide a quantitative molecular framework for examining differential guanine reactivity, sequence-selective oxidative damage, and structure–property relationships in short DNA fragments.

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