Steric Effects on Water Accessability Control Sequence-Selectivity of Radical Cation Reactions in DNA

Abstract

The one-electron oxidation of duplex DNA results in the introduction of a radical cation (electron “hole”) that migrates by a series of short hops and is trapped by an irreversible reaction with water or molecular oxygen. This reaction typically occurs at guanines within Gn sequences where n = 2, 3. It has been generally observed that the 5‘-G of these GG steps is more reactive than the 3‘-G, and this has been explained by means of model calculations to be due to electronic interactions between the two guanines and with adjacent nucleobases. We performed electronic structure calculations on d(5‘-XGGX-3‘)/d(3‘-YCCY-5‘) sequences, where X = A,T,U, and Y is the complementary base. These calculations reveal only a modest preference for the hole to be located on the 5‘-G compared with the 3‘-G. In contrast, molecular dynamics simulations reveal that the distribution of water at the reactive site of the G-radical cation is influenced by its steric environment. In particular, these simulations indicate inhibitio...