Importance of substrate and cofactor polarization in the active site of dihydrofolate reductase
Importance of substrate and cofactor polarization in the active site of dihydrofolate reductase
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DOI：
10.1016/s0022-2836(03)00123-2
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发表时间：
2003-03-21
影响因子：
5.6
通讯作者：
Gao, JL
中科院分区：
文献类型：
--
作者：
Garcia-Viloca, M;Truhlar, DG;Gao, JL
采用量子力学势和分子力学势相结合的分子动力学模拟方法，研究了二氢叶酸还原酶的酶电场对其5-质子化二氢叶酸底物在催化氢化物转移反应的各个阶段的电子极化的影响.配体和酶之间的总静电相互作用能的能量分解表明，极化效应是总静电相互作用能的4%，并且，显着地，它占9千卡/摩尔的过渡态稳定相对于反应物状态。因此，考虑底物极化对于定量解释酶功能和计算抑制剂与蛋白质的结合自由能是必要的。原子极化计算的平均原子电荷的差异在气相中的原子和在分子模拟的酶，这种分析表明，谷氨酸尾巴和蝶呤环是高度极化的基板区域。在酶活性中心的瞬时配置的反应物和产物复合物的电子密度差图证实了部分原子电荷的基础上作出的推论。(C)2003爱思唯尔科技有限公司版权所有。
By using a combined quantum-mechanical and molecular-mechanical potential in molecular dynamics simulations, we have investigated the effects of the enzyme electric field of dihydrofolate reductase on the electronic polarization of its 5-protonated dihydrofolate substrate at various stages of the catalyzed hydride transfer reaction. Energy decomposition of the total electrostatic interaction energy between the ligands and the enzyme shows that the polarization effect is 4% of the total electrostatic interaction energy, and, significantly, it accounts for 9 kcal/mol of transition state stabilization relative to the reactant state. Therefore it is essential to take account of substrate polarization for quantitative interpretation of enzymatic function and for calculation of binding free energies of inhibitors to a protein. Atomic polarizations are calculated as the differences in the average atomic charges on the atoms in gas phase and in molecular simulations of the enzyme; this analysis shows that the glutamate tail and the pterin ring are the highly polarized regions of the substrate. Electron density difference plots of the reactant and product complexes at instantaneous configurations in the enzyme active center confirm the inferences made on the basis of partial atomic charges. (C) 2003 Elsevier Science Ltd. All rights reserved.