The "descriptor energy" values were obtained by a combination of molecular dynamics simulations and quantum chemistry calculations. For each DNA duplex, a 5.0 ns molecular dynamics simulation was conducted, followed by the selection of two conformations based on clustering results from the trajectory. Subsequent operations included the removal of the backbone and non-target bases, the addition of hydrogen atoms at the N1 and N9 positions for both pyrimidine and purine bases, with the residues subjected to the quantum chemistry calculations (Figure ). The mean energy value derived from the two selected conformations was defined as the "descriptor energy". These energies for stacks were found to range from -52.174 to -20.615 kcal/mol (Figure ). Our findings indicate that a higher GC content within the stack domain correlates with lower energy values. Detailed calculation methods and "descriptor energy" values are elaborated in Supplementary Note 2.