SEQUENCE-DEPENDENT THERMODYNAMIC AND QUANTUMCHEMICAL DESCRIPTORS OF DNA DINUCLEOTIDES: AN AM1/MOPAC2016 COMPUTATIONAL STUDY

Abstract

The thermodynamic stability and quantum chemical properties of all sixteen possible DNA dinucleotides (5′-R1R2-3′; R1, R2 = A, C, G, and T) were investigated using the semi-empirical Austin Model-1 (AM1) Hamiltonian as implemented in MOPAC2016. For each fully optimized dinucleotide, the heat of formation, dipole moment, frontier molecular orbital (HOMO and LUMO) energies, and COSMO-derived solventaccessible surface area and molecular volume were calculated. These electronic properties were further employed to derive conceptual density functional theory (DFT)-based global reactivity descriptors, including the HOMO–LUMO energy gap, ionization potential, electron affinity, electronegativity, global hardness, global softness, and chemical potential, and electrophilicity index. The results indicate that purine-initiated dinucleotides, particularly AA, are the least thermodynamically stable and exhibit the greatest electronic reactivity, characterized by the smallest HOMO–LUMO energy gap, lowest global hardness, and lowest electrophilicity index. In contrast, AC and CG possess the largest energy gaps and highest ionization potentials, reflecting enhanced kinetic stability and reduced chemical reactivity. Dinucleotides such as TG and CC are thermodynamically the most stable, whereas TT and GG exhibit the highest electron affinity and electrophilicity index, identifying them as comparatively stronger electrophiles. Molecular size, as represented by COSMO molecular volume and molecular weight, is governed primarily by purine content rather than by sequence order. Overall, these findings provide a quantitative framework for understanding sequence-dependent variations in the thermodynamic stability, electronic structure, and chemical reactivity of DNA dinucleotides, thereby establishing a useful reference for studies of DNA stability, molecular recognition, and nucleic acid–based therapeutic design.