title: A base-independent repair mechanism for DNA glycosylase--no discrimination within the active site.
abstract: The ubiquitous occurrence of DNA damages renders its repair machinery a crucial requirement for the genomic stability and the survival of living organisms. Deficiencies in DNA repair can lead to carcinogenesis, Alzheimer, or Diabetes II, where increased amounts of oxidized DNA bases have been found in patients. Despite the highest mutation frequency among oxidized DNA bases, the base-excision repair process of oxidized and ring-opened guanine, FapydG (2,6-diamino-4-hydroxy-5-formamidopyrimidine), remained unclear since it is difficult to study experimentally. We use newly-developed linear-scaling quantum-chemical methods (QM) allowing us to include up to 700 QM-atoms and achieving size convergence. Instead of the widely assumed base-protonated pathway we find a ribose-protonated repair mechanism which explains experimental observations and shows strong evidence for a base-independent repair process. Our results also imply that discrimination must occur during recognition, prior to the binding within the active site.
authors.affiliation: 1] Chair of Theoretical Chemistry, Department of Chemistry, University of Munich (LMU), Butenandtstr. 7, D-81377 Munich, Germany [2] Center for Integrated Protein Science Munich (CIPSM) at the Department of Chemistry, University of Munich (LMU), Butenandtstr. 5-13, D-81377 Munich, Germany.
authors.forename: Iris D
authors.initials: ID
authors.lastname: Blank
authors.affiliation: 1] Chair of Theoretical Chemistry, Department of Chemistry, University of Munich (LMU), Butenandtstr. 7, D-81377 Munich, Germany [2] Center for Integrated Protein Science Munich (CIPSM) at the Department of Chemistry, University of Munich (LMU), Butenandtstr. 5-13, D-81377 Munich, Germany.
authors.forename: Keyarash
authors.initials: K
authors.lastname: Sadeghian
authors.affiliation: 1] Chair of Theoretical Chemistry, Department of Chemistry, University of Munich (LMU), Butenandtstr. 7, D-81377 Munich, Germany [2] Center for Integrated Protein Science Munich (CIPSM) at the Department of Chemistry, University of Munich (LMU), Butenandtstr. 5-13, D-81377 Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Ochsenfeld
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D045647:DNA Glycosylases / Q000737:chemistry / Q000378:metabolism*; D004260:DNA Repair; D006147:Guanine / Q000737:chemistry; D013294:Lactococcus lactis / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D010084:Oxidation-Reduction; D011743:Pyrimidines / Q000737:chemistry / Q000378:metabolism; D011789:Quantum Theory; D013379:Substrate Specificity
chemical_list: D011743:Pyrimidines; C071023:2,6-diamino-4-hydroxy-5-formamidopyrimidine; D006147:Guanine; D045647:DNA Glycosylases