title: Molecular dynamics simulation of clustered DNA damage sites containing 8-oxoguanine and abasic site.
abstract: Clustered DNA damage sites induced by ionizing radiation have been suggested to have serious consequences to organisms, such as cancer, due to their reduced probability to be repaired by the enzymatic repair machinery of the cell. Although experimental results have revealed that clustered DNA damage sites effectively retard the efficient function of repair enzymes, it remains unclear as to what particular factors influence this retardation. In this study, approaches based on molecular dynamics (MD) simulation have been applied to examine conformational changes and energetic properties of DNA molecules containing clustered damage sites consisting of two lesioned sites, namely 7,8-dihydro-8-oxoguanine (8-oxoG) and apurinic/apyrimidinic (AP) site, located within a few base pairs of each other. After 1 ns of MD simulation, one of the six DNA molecules containing a clustered damage site develops specific characteristic features: sharp bending at the lesioned site and weakening or complete loss of electrostatic interaction energy between 8-oxoG and bases located on the complementary strand. From these results it is suggested that these changes would make it difficult for the repair enzyme to bind to the lesions within the clustered damage site and thereby result in a reduction of its repair capacity.
authors.affiliation: Division of Radiological Protection and Biology, National Institute of Infectious Diseases, Tokyo, Japan. fuj@nih.go.jp
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Fujimoto
authors.forename: Miroslav
authors.initials: M
authors.lastname: Pinak
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Nemoto
authors.forename: Peter
authors.initials: P
authors.lastname: O'Neill
authors.forename: Etsuo
authors.initials: E
authors.lastname: Kume
authors.forename: Kimiaki
authors.initials: K
authors.lastname: Saito
authors.forename: Hideaki
authors.initials: H
authors.lastname: Maekawa
mesh_terms: D000465:Algorithms; D001080:Apurinic Acid / Q000737:chemistry; D001483:Base Sequence; D003198:Computer Simulation; D004249:DNA Damage; D004260:DNA Repair; D006151:Guanosine / Q000031:analogs & derivatives* / Q000737:chemistry*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D011119:Polynucleotides / Q000737:chemistry; D011839:Radiation, Ionizing; D013816:Thermodynamics
chemical_list: D011119:Polynucleotides; C001790:apyrimidinic acid; D001080:Apurinic Acid; D006151:Guanosine; C046215:8-hydroxyguanosine