Key Lab of Colloid and Interface Chemistry, Ministry of Education, School of Chemistry and Chemical Engineering, Shandong University, Jinan, Shandong 250100, China.
J Phys Chem B. 2010 Nov 25;114(46):15296-300. doi: 10.1021/jp106714m. Epub 2010 Nov 1.
Combined quantum-mechanical/molecular-mechanical (QM/MM) approaches have been applied to investigate the detailed reaction mechanism of human O(6)-alkylguanine-DNA alkyltransferase (AGT). AGT is a direct DNA repair protein that is capable of repairing alkylated DNA by transferring the methyl group to the thiol group of a cysteine residue (Cys145) in the active site in an irreversible and stoichiometric reaction. Our QM/MM calculations reveal that the methyl group transferring step is expected to occur through two steps, in which the methyl carbocation generating step is the rate-determining step with an energy barrier of 14.4 kcal/mol at the QM/MM B3LYP/6-31G(d,p)//CHARMM22 level of theory. It is different from the previous theoretical studies based on QM calculations by using a cluster model in which the methyl group transferring step is a one-step process with a higher energy barrier.
联合量子力学/分子力学（QM/MM）方法已被应用于研究人类 O(6)-烷基鸟嘌呤-DNA 烷基转移酶（AGT）的详细反应机制。AGT 是一种直接的 DNA 修复蛋白，能够通过将甲基转移到活性位点中半胱氨酸残基（Cys145）的巯基上来不可逆和计量地修复烷基化 DNA。我们的 QM/MM 计算表明，甲基转移步骤预计通过两个步骤发生，其中生成甲基碳正离子的步骤是速率决定步骤，在 QM/MM B3LYP/6-31G(d,p)//CHARMM22 理论水平下的能垒为 14.4 kcal/mol。这与以前基于使用团簇模型的 QM 计算的理论研究不同，其中甲基转移步骤是一个具有更高能垒的一步过程。
