Structural Damages of the Dodecamer B-DNA Induced by N3 Protonation of Cytosine and Oxidation/Nitration of Guanine: A ReaxFF Reactive Molecular Dynamics Simulation

Abstract

DNA can be protonated in an acidic microenvironment and therefore may undergo denaturation. Specially, during photodynamic therapy, which usually proceeds via oxidation and nitration of the DNA bases of the cancer cells, protonation may result in DNA structural deformation and consequently accelerate its denaturation and destruction. In the present study, the effect of the protonation of cytosine (at N3), along with the oxidation/nitration of guanine, on the structural instability and possible denaturation of the double-strand dodecamer B-DNA has been investigated using ReaxFF reactive molecular dynamics (RMD) simulations. Results of these RMD simulations show that protonation has a larger impact on the oxo/nitro-modified B-DNA as compared to that on its pristine structure. In addition, cytosine protonation (at N3) imposes higher stress on the dodecamer structure in the modified 8-nitroguanine B-DNA system compared to that in the other two modified systems, 5-guanidino-4-nitroimidazole and 8-oxoguanine B-DNA. Detailed analysis of the results of the RMD simulations shows that protonation of modified 8-nitroguanine B-DNA results in a higher structural fluctuation such that the number of the interstrand hydrogen bonds decreases and water molecules find larger spaces to diffuse into the weakened double-strand structure and cause further expansion (both in width and length) of the B-DNA structure. While all modifications and protonations have been applied on the GC nucleobase pairs of the B-DNA molecule, their effects are more evident over the farther AT (7th) nucleobase pair, which belongs to the GAATTC section of the B-DNA double helix named EcoRI, already known to be sensitive to any alteration in the B-DNA molecule. Our RMD simulations also show that this AT (7th) nucleobase pair is separated in the three modified B-DNA systems having N3-protonated cytosines, N3-protonated cytosine and 8-nitroguanine, and N3-protonated cytosine and 5-guanidino-4-nitroimidazole. As a conclusion, it can be suggested that denaturation of the dodecamer B-DNA molecule starts probably from the EcoRI section of the molecule due to the breakage of the hydrogen bonds of its AT nucleobase pair. © 2025 American Chemical Society