Cross-linking between thymine and indolyl radical: possible mechanisms for cross-linking of DNA and tryptophan-containing peptides.
As experimentally observed in gamma-irradiated aqueous solutions of tryptophan-containing peptides in the presence of DNA, a fast electron (or hydrogen atom) transfer from the DNA restores an intact tryptophan residue at the expense of the DNA integrity. Alternatively, addition of the deprotonated electron-deficient indolyl radical to the DNA, followed by subsequent rearrangement, may lead toward DNA/tryptophan-containing peptide cross-linking. Herein, possible reaction mechanisms for thymine-indolyl radical cross-linking are proposed. The consistent use of the contact spin density distribution is the key virtue of this work. The Becke 3, Lee, Yang, and Parr (B3LYP) density functional theory (DFT) method is employed to investigate the feasibility of the proposed cross-linking mechanisms. A possible complete reaction mechanism consists of a combination of the C(5)-hydroxylated thymine and indolyl radicals forming the initial cross-linked product, a hydrogen transfer within the initial cross-linked product by use of a bridging water molecule, and a dehydration step. The overall thermodynamics of the free energy profiles at 0 and 298 K are similar and display differences of magnitude for the hydrogen-transfer reaction. Temperature may be a key factor influencing the overall mechanism. The skeletal structures and contact spin densities on the heavy atoms of the tryptophan side chain and indolyl radicals are essentially equal. Hence, it is believed that a direct combination of the C(5)-hydroxylated thymine and tryptophan radicals should form the initial cross-linked product, as far as addition of the tryptophan radical to the DNA is concerned.
Mitrasinovic
Petar M
PM
Department of Chemistry, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4J3. pmitrasinovic@yahoo.ca
D003432:Cross-Linking Reagents / Q000737:chemistry*; D004247:DNA / Q000737:chemistry*; D005609:Free Radicals / Q000737:chemistry*; D006859:Hydrogen / Q000737:chemistry; D006900:Hydroxylation; D007211:Indoles / Q000737:chemistry*; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry*; D013816:Thermodynamics; D013941:Thymine / Q000737:chemistry*; D014364:Tryptophan / Q000737:chemistry*
D003432:Cross-Linking Reagents; D005609:Free Radicals; D007211:Indoles; D010455:Peptides; D006859:Hydrogen; D014364:Tryptophan; D004247:DNA; D013941:Thymine