Quantum chemical challenge to elucidate the functional mechanism of base sequence specificity deciding removal of the DNA damage

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K22903
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 63:Environmental analyses and evaluation and related fields
• Research Institution: Tohoku University
• Principal Investigator: Suzuki Ai 東北大学, 未来科学技術共同研究センター, 准教授 (40463781)
• Co-Investigator(Kenkyū-buntansha): 安井 学 国立医薬品食品衛生研究所, 変異遺伝部, 室長 (50435707)
• Project Period (FY): 2019-06-28 – 2022-03-31
• Keywords: 水 / 8-オキソグアニン / DNA / 塩基配列

Outline of Final Research Achievements

A mutagenic lesion, 7, 8-dihydro-8-oxoguanine (8oxoG) is generated by oxidative stress. The DNA (deoxyribonucleic acid) glycosylases as typified by the human repair enzyme 8-oxoguanine glycosylase (hOGG1) are known to act particularly on the single 8oxoG legions and remove them. The hOGG1 plays a catalytic role in the enzymic reaction process by rotating and cleaving N-glycosidic bond of the 8oxoG nucleoside. Each electronic configuration around the single 8oxoG lesion as well as one-nucleotide apart tandem 8oxoG legions in the DNA with surrounding water network is compared with that of undamaged DNA at body temperature by an accelerated quantum-chemical method. Tandem 8oxoG lesions which sandwich one adenine have cross-binding hydrogen bonds along the helical axis between the hydrogen and the adducted oxygen and fix individual lesions, keeping them secured in the helix. Eversion of 8oxoG for enzymic catalyzation is difficult to take in the case of the clustered 8oxoG lesions.

Free Research Field

生体分子の計算

Academic Significance and Societal Importance of the Research Achievements

ＤＮＡの損傷除去や修復過程は、ＤＮＡ塩基配列固有の水分子の運動性や配向にも依存し修復時に酵素に密着する際の構造であるＤＮＡの屈曲性や損傷の除去率に影響すると考えられる。ＤＮＡの損傷がピンポイントでは無く広範囲に及ぶ場合、その損傷領域を一体として捉えることに意義があるため、必然的に計算領域も広範囲にわたり、周辺水分子も含めて原子数の多さ故に計算負荷も大きくなる。広範囲にわたる損傷の大きさをそのまま捉えながら無傷と比較検証するために高速な量子分子動力学法を適用することは生体構成分子に対する現実的な理論計算手法の適用という観点からも学術的な意義が大きい.