title: Energetic preference of 8-oxoG eversion pathways in a DNA glycosylase.
abstract: Base eversion is a fundamental process in the biochemistry of nucleic acids, allowing proteins engaged in DNA repair and epigenetic modifications to access target bases in DNA. Crystal structures reveal end points of these processes, but not the pathways involved in the dynamic process of base recognition. To elucidate the pathway taken by 8-oxoguanine during base excision repair by Fpg, we calculated free energy surfaces during eversion of the damaged base through the major and minor grooves. The minor groove pathway and free energy barrier (6-7 kcal/mol) are consistent with previously reported results (Qi, Y.; Spong, M. C.; Nam, K.; Banerjee, A.; Jiralerspong, S.; Karplus, M.; Verdine, G. L. Nature 2009, 462, 762.) However, eversion of 8-oxoG through the major groove encounters a significantly lower barrier (3-4 kcal/mol) more consistent with experimentally determined rates of enzymatic sliding during lesion search (Blainey, P. C.; van Oijent, A. M.; Banerjee, A.; Verdine, G. L.; Xie, X. S. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 5752.). Major groove eversion has been suggested for other glycosylases, suggesting that in addition to function, dynamics of base eversion may also be conserved.
authors.affiliation: Department of Chemistry, Stony Brook University, Stony Brook, New York 11794-2700, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Bergonzo
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Campbell
authors.forename: Carlos
authors.initials: C
authors.lastname: de los Santos
authors.forename: Arthur P
authors.initials: AP
authors.lastname: Grollman
authors.forename: Carlos
authors.initials: C
authors.lastname: Simmerling
mesh_terms: D045647:DNA Glycosylases / Q000737:chemistry / Q000378:metabolism*; D004260:DNA Repair; D043382:DNA-Formamidopyrimidine Glycosylase / Q000737:chemistry / Q000378:metabolism; D006147:Guanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D056004:Molecular Dynamics Simulation; D011387:Prokaryotic Cells / Q000201:enzymology; D013816:Thermodynamics
chemical_list: C024829:8-hydroxyguanine; D006147:Guanine; D045647:DNA Glycosylases; D043382:DNA-Formamidopyrimidine Glycosylase