title: Single Amino Acid Mutation Controls Hole Transfer Dynamics in DNA-Methyltransferase HhaI Complexes.
abstract: Different mutagenic effects are generated by DNA oxidation that implies the formation of radical cation states (so-called holes) on purine nucleobases. The interaction of DNA with proteins may protect DNA from oxidative damage owing to hole transfer (HT) from the stack to aromatic amino acids. However, how protein binding affects HT dynamics in DNA is still poorly understood. Here, we report a computational study of HT in DNA complexes with methyltransferase HhaI with the aim of elucidating the molecular factors that explain why long-range DNA HT is inhibited when the glutamine residue inserted in the double helix is mutated into a tryptophan. We combine molecular dynamics, quantum chemistry, and kinetic Monte Carlo simulations and find that protein binding stabilizes the energies of the guanine radical cation states and significantly impacts the corresponding electronic couplings, thus determining the observed behavior, whereas the formation of a tryptophan radical leads to less efficient HT.
authors.affiliation: Departament de Fisicoquímica, Facultat de Farmàcia, Universitat de Barcelona , Av. Joan XXIII s/n, 08028 Barcelona, Spain.
authors.forename: Marina
authors.initials: M
authors.lastname: Corbella
authors.affiliation: Institució Catalana de Recerca i Estudis Avançats (ICREA) , 08010 Barcelona, Spain.|Institut de Química Computacional i Catàlisi and Departament de Química, Universitat de Girona , Campus Montilivi, 17071 Girona, Spain.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Voityuk
authors.affiliation: Departament de Fisicoquímica, Facultat de Farmàcia, Universitat de Barcelona , Av. Joan XXIII s/n, 08028 Barcelona, Spain.
authors.forename: Carles
authors.initials: C
authors.lastname: Curutchet
mesh_terms: D019943:Amino Acid Substitution; D000596:Amino Acids / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015257:DNA-Cytosine Methylases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D009010:Monte Carlo Method; D009154:Mutation; D010084:Oxidation-Reduction; D011789:Quantum Theory
chemical_list: D000596:Amino Acids; D004247:DNA; C037664:DNA modification methylase HhaI; D015257:DNA-Cytosine Methylases
keywords: DNA damage; INDO/S; charge transfer; methyltransferase HhaI; molecular dynamics