Gauging the flexibility of the active site in soybean lipoxygenase-1 (SLO-1) through an atom-centered density matrix propagation (ADMP) treatment that facilitates the sampling of rare events.
Gauging the flexibility of the active site in soybean lipoxygenase-1 (SLO-1) through an atom-centered density matrix propagation (ADMP) treatment that facilitates the sampling of rare events.
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通过以原子为中心的密度矩阵传播 (ADMP) 处理来测量大豆脂氧合酶-1 (SLO-1) 活性位点的灵活性，该处理有利于罕见事件的采样。
DOI：
10.1021/jp3015047
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Iyengar,SrinivasanS
中科院分区：
文献类型：
--
作者：
Phatak,Prasad;Sumner,Isaiah;Iyengar,SrinivasanS
我们提出了一种计算方法来采样大型生物酶中的罕见事件，这些事件可能涉及电子极化的反应过程。该方法包括电子自由度和核自由度的同时动力学处理，其中电子部分的贡献使用混合密度泛函理论计算，并通过混合量子力学/分子力学(QM/MM)处理来降低计算成本。因此，本文涉及对罕见事件的QM/MM动力学处理。应用该方法研究了大豆脂氧合酶-1(SLO-1)催化亚油酸氧化反应中活性中心元素对临界氢转移步骤的影响。研究发现，活性中心的动态涨落和相关的柔性对于维持静电在能够顺利发生反应过程的区域内是至关重要的。为限制活性中心灵活性而强制实施的物理限制类似于突变，在所研究的情况下，对静电波动有不利影响，从而对氢转移过程产生不利影响。
We present a computational methodology to sample rare events in large biological enzymes that may involve electronically polarizing, reactive processes. The approach includes simultaneous dynamical treatment of electronic and nuclear degrees of freedom, where contributions from the electronic portion are computed using hybrid density functional theory and the computational costs are reduced through a hybrid quantum mechanics/molecular mechanics (QM/MM) treatment. Thus, the paper involves a QM/MM dynamical treatment of rare events. The method is applied to probe the effect of the active site elements on the critical hydrogen transfer step in the soybean lipoxygenase-1 (SLO-1) catalyzed oxidation of linoleic acid. It is found that the dynamical fluctuations and associated flexibility of the active site are critical toward maintaining the electrostatics in the regime where the reactive process can occur smoothly. Physical constraints enforced to limit the active site flexibility are akin to mutations and, in the cases studied, have a detrimental effect on the electrostatic fluctuations, thus adversely affecting the hydrogen transfer process.