质子网络的灵活性使类固醇异构酶活性位点具有鲁棒性和大电场
Proton network flexibility enables robustness and large electric fields in the ketosteroid isomerase active site
摘要：
氢键网络在从蛋白质折叠到酶催化的生物学功能中起着至关重要的作用。在这里，我们结合电子结构计算和从头算路径积分分子动力学模拟，其中包括核和电子量子效应，以显示为什么网络的短氢键的活性位点的甾酮异构酶是非常强大的突变沿网络，以及如何产生大的本地电场。我们证明，这些属性产生的网络的能力，以响应通过移动质子的位置和重新分配电子电荷密度的扰动。这种灵活性导致性质的微小变化，例如残基的部分电离和残基突变后的$pK_a$同位素效应，与最近的实验一致。这种质子的灵活性进一步增强时，在存在的中间类似物，这使我们能够解释在最近的实验中观察到的酶的活性位点的大电场的化学起源的扩展的氢键网络的形式。
英文摘要：
Hydrogen bond networks play vital roles in biological functions ranging from protein folding to enzyme catalysis. Here we combine electronic structure calculations and ab initio path integral molecular dynamics simulations, which incorporate both nuclear and electronic quantum effects, to show why the network of short hydrogen bonds in the active site of ketosteroid isomerase is remarkably robust to mutations along the network and how this gives rise to large local electric fields. We demonstrate that these properties arise from the network's ability to respond to a perturbation by shifting proton positions and redistributing electronic charge density. This flexibility leads to small changes in properties such as the partial ionization of residues and $pK_a$ isotope effects upon mutation of the residues, consistent with recent experiments. This proton flexibility is further enhanced when an extended hydrogen bond network forms in the presence of an intermediate analog, which allows us to explain the chemical origins of the large electric fields in the enzyme's active site observed in recent experiments.
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