Development of a QM/MM(ABEEM) method for the deprotonation of neutral and cation radicals in the G-tetrad and GGX(8-oxo-G) tetrad

The rapid deprotonation of G&z.rad; + in the DNA strand impedes positive charge (hole) transfer, whereas the slow deprotonation rate of G&z.rad; + in the G-tetrad makes it a more suitable carrier for hole conduction. The QM/MM(ABEEM) combined method, which involves the integration of QM and the ABEEM polarizable force field (ABEEM PFF), was developed to investigate the deprotonation of neutral and cation free radicals in the G-tetrad and GGX(8-oxo-G) tetrad (xanthine and 8-oxoguanine dual substituted G-tetrad). By incorporating valence-state electronegativity piecewise functions χ *( r ) and implementing charge local conservation conditions, QM/MM(ABEEM) possesses the advantage of accurately simulating charge transfer and polarization effect during deprotonation. The activation energy calculated by the QM method of X&z.rad; is the lowest among other bases in the GGX(8-oxo-G) tetrad, which is supported by the computation of the average electronegativity calculated by ABEEM PFF. By utilizing QM/MM(ABEEM) with a two-way free energy perturbation method, the deprotonation activation energy of X&z.rad; in the GGX(8-oxo-G) tetrad is determined to be 33.0 ± 2.1 kJ mol −1 , while that of G&z.rad; + in the G-tetrad is 20.7 ± 0.6 kJ mol −1 , consistent with the experimental measurement of 20 ± 1.0 kJ mol −1 . These results manifest that X&z.rad; in the GGX(8-oxo-G) tetrad exhibits a slower deprotonation rate than G&z.rad; + in the G-tetrad, suggesting that the GGX(8-oxo-G) tetrad may serve as a more favorable hole transport carrier. Furthermore, the unequal average electronegativities of bases in the GGX(8-oxo-G) tetrad impede the deprotonation rate. This study provides a potential foundation for investigating the microscopic mechanism of DNA electronic devices. The unequal average electronegativity within GGX(8-oxo-G) tetrad impedes deprotonation and reduces competition with hole transfer, ultimately enhancing hole transfer efficiency.