Guanine radical cation (G•+) is a key intermediate in many oxidative processes occurring in nucleic acids. Here, by combining mixed Quantum Mechanical/Molecular Mechanics calculations and Molecular Dynamics (MD) simulations, we study how the structural behaviour of a tract GGG(TTAGGG)3 (hereafter Tel21) of the human telomeric sequence, folded in an antiparallel quadruple helix, changes when one of the G bases is ionized to G•+ (Tel21+). Once assessed that the electron-hole is localized on a single G, we perform MD simulations of twelve Tel21+ systems, differing in the position of G•+ in the sequence. When G•+ is located in the tetrad adjacent to the diagonal loop, we observe substantial structural rearrangements, which can decrease the electrostatic repulsion with the inner Na+ ions and increase the solvent exposed surface of G•+. Analysis of solvation patterns of G•+ provides new insights on the main reactions of G•+, i.e. the deprotonation at two different sites and hydration at the C8 atom, the first steps of the processes producing 8oxo-Guanine. We suggest the main structural determinants of the relative reactivity of each position and our conclusions, consistent with the available experimental trends, can help rationalizing the reactivity of other G-quadruplex topologies.

Departamento de Quimica Facultad de Ciencias and Institute for Advanced Research in Chemistry Universidad Autonoma de Madrid Campus de Excelencia UAM CSIC 28049 Madrid Spain

Institute of Biophysics of the Czech Academy of Sciences Královopolská 135 612 65 Brno Czech Republic

Istituto Biostrutture e Bioimmagini Consiglio Nazionale delle Ricerche Via Mezzocannone 16 80136 Napoli Italy

Regional Centre of Advanced Technologies and Materials Czech Advanced Technology and Research Institute Palacký University Křížkovského 8 779 00 Olomouc Czech Republic

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