山本 典史, Life (2022)
Free-energy profile analysis of the catalytic Reaction of glycinamide ribonucleotide synthetase
山本 典史 / 三瓶 嚴一(1) / 河合 剛太(2)
- 電気通信大学 大学院 情報理工学研究科 基盤理工学専攻
- 千葉工業大学 先進工学部 生命科学科
The second step in the de novo biosynthetic pathway of purine is catalyzed by PurD, which consumes an ATP molecule to produce glycinamide ribonucleotide (GAR) from glycine and phosphoribosylamine (PRA). PurD initially reacts with ATP to produce an intermediate, glycyl-phosphate, which then reacts with PRA to produce GAR. The structure of the glycyl-phosphate intermediate bound to PurD has not been determined. Therefore, the detailed reaction mechanism at the molecular level is unclear. Here, we developed a computational protocol to analyze the free-energy profile for the glycine phosphorylation process catalyzed by PurD, which examines the free-energy change along a minimum energy path based on a perturbation method combined with the quantum mechanics and molecular mechanics hybrid model. Further analysis revealed that during the formation of glycyl-phosphate, the partial atomic charge distribution within the substrate molecules was not localized according to the formal charges, but was delocalized overall, which contributed significantly to the interaction with the charged amino acid residues in the ATP-grasp domain of PurD.