Tian Li, Friesner Richard A
Department of Chemistry, Columbia University, New York, New York 10027.
J Chem Theory Comput. 2009;5(5):1421-1431. doi: 10.1021/ct900040n.
Using a structure generated by induced fit modeling of the protein-ligand complex, the reaction path for hydrogen atom abstraction in P450 BM3 is studied by means of mixed QM/MM methods to determine the structures and energetics along the reaction path. The IFD structure is suitable for hydrogen atom abstraction at the ω-1 position. The electronic structures obtained are similar to those observed in P450 cam. We show that the barrier for the hydrogen abstraction step from QM/MM modeling is 13.3 kcal/mol in quartet and 15.6 kcal/mol in doublet. Although there is some strain energy present in the ligand, the activation barrier is not dramatically affected. A crystal water molecule, HOH502, plays a role as catalyst and decreases the activation barrier by about 2 kcal/mol and reaction energy by about 3-4 kcal/mol. In order to achieve reactive chemistry at the remaining experimentally observed positions in the hydrocarbon tail of the ligand, other structures would have to be utilized as a starting point for the reaction. Finally, the present results still leave open the question of whether DFT methods provide an accurate computation of the barrier height in the P450 hydrogen atom abstraction reaction.
利用蛋白质-配体复合物诱导契合建模生成的结构，采用混合量子力学/分子力学（QM/MM）方法研究了P450 BM3中氢原子提取的反应路径，以确定沿反应路径的结构和能量。诱导契合结构适用于ω-1位的氢原子提取。得到的电子结构与P450 cam中观察到的相似。我们表明，从QM/MM建模得到的氢提取步骤的四重态势垒为13.3 kcal/mol，二重态势垒为15.6 kcal/mol。尽管配体中存在一些应变能，但活化势垒并未受到显著影响。一个结晶水分子HOH502起到催化剂的作用，使活化势垒降低约2 kcal/mol，反应能量降低约3-4 kcal/mol。为了在配体烃尾中其余实验观察到的位置实现反应化学，必须使用其他结构作为反应的起点。最后，目前的结果仍然没有解决密度泛函理论（DFT）方法是否能准确计算P450氢原子提取反应中势垒高度的问题。
