Abstract:
Six water molecules have been used for microsolvation to outline a hydrogen bonded network around
complexes of ethylene epoxide with nucleotide bases adenine (EAw), guanine (EGw) and cytosine
(ECw). These models have been developed with the MPWB1K-PCM/6-311++G(3df,2p)//MPWB1K/
6-31+G(d,p) level of DFT method and calculated SN2 type ring opening of the epoxide due to amino
group of the nucleotide bases, viz. the N6 position of adenine, N2 position of guanine and N4 position
of cytosine. Activation energy (Eact) for the ring opening was found to be 28.06, 28.64, and
28.37 kcal mol-1 respectively for EAw, EGw and ECw. If water molecules were not used, the reactions
occurred at considerably high value of Eact, viz. 53.51 kcal mol-1 for EA, 55.76 kcal mol-1 for EG and
56.93 kcal mol-1 for EC. The ring opening led to accumulation of negative charge on the developing
alkoxide moiety and the water molecules around the charge localized regions showed strong hydrogen
bond interactions to provide stability to the intermediate systems EAw-1, EGw-1 and ECw-1. This led
to an easy migration of a proton from an activated water molecule to the alkoxide moiety to generate a
hydroxide. Almost simultaneously, a proton transfer chain reaction occurred through the hydrogen
bonded network of water molecules and resulted in the rupture of one of the N–H bonds of the
quaternized amino group. The highest value of Eact for the proton transfer step of the reaction was
2.17 kcal mol-1 for EAw, 2.93 kcal mol-1 for EGw and 0.02 kcal mol-1 for ECw. Further, the overall
reaction was exothermic by 17.99, 22.49 and 13.18 kcal mol-1 for EAw, EGw and ECw, respectively,
suggesting that the reaction is irreversible. Based on geometric features of the epoxide–nucleotide base
complexes and the energetics, the highest reactivity is assigned for adenine followed by cytosine and
guanine. Epoxide-mediated damage of DNA is reported in the literature and the present results suggest
that hydrated DNA bases become highly SN2 active on epoxide systems and the occurrence of such
reactions can inflict permanent damage to the DNA
