title: Computational Study of Oxidation of Guanine by Singlet Oxygen (1Δg) and Formation of Guanine:Lysine Cross-Links.
abstract: Oxidation of guanine in the presence of lysine can lead to guanine-lysine cross-links. The ratio of the C4, C5 and C8 crosslinks depends on the manner of oxidation. Type II photosensitizers such as Rose Bengal and methylene blue can generate singlet oxygen, which leads to a different ratio of products than oxidation by type I photosensitizers or by one electron oxidants. Modeling reactions of singlet oxygen can be quite challenging. Reactions have been explored using CASSCF, NEVPT2, DFT, CCSD(T), and BD(T) calculations with SMD implicit solvation. The spin contamination in open-shell calculations were corrected by Yamaguchi's approximate spin projection method. The addition of singlet oxygen to guanine to form guanine endo- peroxide proceeds step-wise via a zwitterionic peroxyl intermediate. The subsequent barrier for ring closure is smaller than the initial barrier for singlet oxygen addition. Ring opening of the endoperoxide by protonation at C4-O is followed by loss of a proton from C8 and dehydration to produce 8-oxoGox. The addition of lysine (modelled by methylamine) or water across the C5=N7 double bond of 8-oxoGoxis followed by acyl migration to form the final spiro products. The barrier for methylamine addition is significantly lower than for water addition and should be the dominant reaction channel. These results are in good agreement with the experimental results for the formation of guanine-lysine cross-links by oxidation by type II photosensitizers.
authors.affiliation: Chemistry Department, Wayne State University, Detroit, Michigan, 48202, USA.
authors.forename: Bishnu
authors.initials: B
authors.lastname: Thapa
authors.affiliation: Chemistry Department, Wayne State University, Detroit, Michigan, 48202, USA.
authors.forename: Barbara H
authors.initials: BH
authors.lastname: Munk
authors.affiliation: Chemistry Department, University of Utah, Salt Lake City, Utah, 84112, USA.
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Burrows
authors.affiliation: Chemistry Department, Wayne State University, Detroit, Michigan, 48202, USA.
authors.forename: H Bernhard
authors.identifier: http://orcid.org/0000-0001-7114-2821
authors.initials: HB
authors.lastname: Schlegel
mesh_terms: D061565:Cycloaddition Reaction; D053138:Cyclohexenes / Q000737:chemistry; D006147:Guanine / Q000737:chemistry*; D008239:Lysine / Q000737:chemistry*; D008744:Methylamines / Q000737:chemistry; D010084:Oxidation-Reduction; D017319:Photosensitizing Agents / Q000737:chemistry; D026082:Singlet Oxygen / Q000737:chemistry*; D013816:Thermodynamics; D014867:Water / Q000737:chemistry
chemical_list: D053138:Cyclohexenes; D008744:Methylamines; D017319:Photosensitizing Agents; D014867:Water; D026082:Singlet Oxygen; D006147:Guanine; C027451:methylamine; C034005:1,3-cyclohexadiene; D008239:Lysine
keywords: DNA; DNA-protein cross-link; endoperoxide; guanine; singlet oxygen