Models for dioxygen activation by the CuB site of dopamine β-monooxygenase and peptidylglycine α-hydroxylating monooxygenase
Models for dioxygen activation by the CuB site of dopamine β-monooxygenase and peptidylglycine α-hydroxylating monooxygenase
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DOI：
10.1007/s00775-005-0066-5
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发表时间：
2006-03-01
影响因子：
3
通讯作者：
Cramer, CJ
中科院分区：
文献类型：
--
作者：
Gherman, BF;Heppner, DE;Cramer, CJ
根据多巴胺 β-单加氧酶和肽酰甘氨酸 α-羟基化单加氧酶 (PHM) 的光谱和晶体学数据，多种配体组已用于模拟这些酶中的氧结合铜位点。采用密度泛函和多参考二阶微扰理论方法相结合的计算提供了对支持 eta(1) 超氧配位的最佳配体集的见解，如 PHM 预催化 Cu/O-2 配合物的晶体结构所示（Prigge 等人，《Science》304：864-867，2004）。阴离子配体设置稳定的eta(2)双氧配位，并发现可产生更多类似过氧的Cu-O-2配合物，具有相对放能的结合自由能，这表明这些加合物可能对底物不发生反应。另一方面，中性配体组（包括一组两个咪唑和一个硫醚）大力支持 eta(1) 双氧配位，并表现出有限的双氧还原。中性配体组支持的 Cu 1:1 加合物的结合自由能也高于其阴离子对应物。最相似模型的几何形状和能量学与 PHM 晶体结构之间的偏差表明蛋白质环境影响 Cu-B 位点的配位几何形状，并增加了与预氧化还原形式结合的水的不稳定性。另一个含义是，为了稳定 eta(1) 双氧配位，中性配体组在仿生模型中至关重要。
On the basis of spectroscopic and crystallographic data for dopamine beta-monooxygenase and peptidylglycine alpha-hydroxylating monooxygenase (PHM), a variety of ligand sets have been used to model the oxygen-binding Cu site in these enzymes. Calculations which employed a combination of density functional and multireference second-order perturbation theory methods provided insights into the optimal ligand set for supporting eta(1) superoxo coordination as seen in a crystal structure of a precatalytic Cu/O-2 complex for PHM (Prigge et al. in Science 304:864-867, 2004). Anionic ligand sets stabilized eta(2) dioxygen coordination and were found to lead to more peroxo-like Cu-O-2 complexes with relatively exergonic binding free energies, suggesting that these adducts may be unreactive towards substrates. Neutral ligand sets (including a set of two imidazoles and a thioether), on the other hand, energetically favored eta(1) dioxygen coordination and exhibited limited dioxygen reduction. Binding free energies for the 1:1 adducts with Cu supported by the neutral ligand sets were also higher than with their anionic counterparts. Deviations between the geometry and energetics of the most analogous models and the PHM crystal structures suggest that the protein environment influences the coordination geometry at the Cu-B site and increases the lability of water bound to the preoxygenated reduced form. Another implication is that a neutral ligand set will be critical in biomimetic models in order to stabilize eta(1) dioxygen coordination.