A DFT-based QM-MM approach designed for the treatment of large molecular systems:: Application to chorismate mutase
A DFT-based QM-MM approach designed for the treatment of large molecular systems:: Application to chorismate mutase
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DOI：
10.1021/jp036236h
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发表时间：
2003-12-11
影响因子：
3.3
通讯作者：
Estrin, DA
中科院分区：
文献类型：
--
作者：
Crespo, A;Scherlis, DA;Estrin, DA
我们提出了一种密度泛函理论 (DFT) 混合量子力学/分子力学 (QM-MM) 实现，专为复杂环境中的反应模拟而开发。它特别适合研究凝聚相中的酶活性位点或溶质。该方法将溶质的 QM 描述与环境的 MM 处理相结合。 QM 片段使用 DFT 进行处理，如在计算高效的程序 SIESTA 中实现的那样，而环境则使用 Wang 等人的方法进行处理。琥珀色力场参数化。我们应用新的 QM-MM 方案通过计算真空、水溶液和枯草芽孢杆菌分支酸变位酶活性位点的反应能量分布来研究分支酸向预苯酯的转化。我们在酶模拟中对 QM 子系统的两种不同选择进行了计算：分别包括仅底物部分和底物加上带电侧链 glu78 和 arg90。在这两种情况下，我们的结果与实验非常吻合。相对于溶液中的未催化反应，分支酸变位酶所实现的催化活性是由于压缩导致的底物分子的轻微不稳定以及过渡态的主要静电稳定，这降低了反应的活化能。
We present a density functional theory (DFT) hybrid quantum mechanical/molecular mechanical (QM-MM) implementation developed for simulations of reactions in complex environments. It is particularly suited to study enzyme active sites or solutes in condensed phases. The method combines a QM description of the solute with a MM treatment of the environment. The QM fragment is treated using DFT as implemented in the computationally efficient program SIESTA, while the environment is treated using the Wang et al. Amber force field parametrization. We applied our new QM-MM scheme to study the conversion of chorismate to prephenate by computing the reaction energy profile in vacuo, aqueous solution and in the active site of the B. subtilis chorismate mutase enzyme. We have performed calculations for two different choices of the QM subsystem in the enzyme simulations: including only the substrate moiety and the substrate plus the charged side chains glu78 and arg90, respectively. In both cases, our results are in good agreement with experiment. The catalytic activity achieved by chorismate mutase relative to the uncatalyzed reaction in solution is due to both a minor destabilization of the substrate molecule by compression and a major electrostatic stabilization of the transition state, which reduce the activation energy of the reaction.