Hybrid Quantum and Classical Simulations of the Dihydrofolate Reductase Catalyzed Hydride Transfer Reaction on an Accurate Semi-Empirical Potential Energy Surface
Hybrid Quantum and Classical Simulations of the Dihydrofolate Reductase Catalyzed Hydride Transfer Reaction on an Accurate Semi-Empirical Potential Energy Surface
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DOI：
10.1021/ct2004808
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发表时间：
2011-10-01
影响因子：
5.5
通讯作者：
Wu, Xin
中科院分区：
文献类型：
--
作者：
Doron, Dvir;Major, Dan Thomas;Wu, Xin
二氢叶酸还原酶（DHFR）催化烟酰胺腺嘌呤二核苷酸磷酸氢化物（NADPH）还原7，8-二氢叶酸，生成5，6，7，8-四氢叶酸和氧化烟酰胺。DHFR是一种小的，灵活的，单体蛋白质，没有金属或SS键，并作为一种酶，通常用于检查酶学的基本方面。在目前的工作中，我们提出了广泛的基准计算在气相中的几个模型反应是相关的DHFR催化氢化物转移。为此，我们采用G4 MP2和CBS-QB 3从头计算以及众多的密度泛函理论方法。利用这些结果，我们开发了两个特定的反应参数（SRP）哈密顿半经验AM 1方法的基础上。第一代SRP汉密尔顿算子不考虑色散，而第二代SRP通过AM 1核心排斥函数隐式地考虑色散。这些SRP半经验哈密顿随后用于混合量子力学/分子力学模拟的DHFR催化反应。最后，动力学同位素效应计算使用质量扰动为基础的路径积分方法。
Dihydrofolate reductase (DHFR) catalyzes the reduction of 7,8-dihydrofolate by nicotinamide adenine dinucleotide phosphate hydride (NADPH) to form 5,6,7,8-tetrahydrofolate and oxidized nicotinamide. DHFR is a small, flexible, monomeric protein with no metals or SS bonds and serves as one of the enzymes commonly used to examine basic aspects in enzymology. In the current work, we present extensive benchmark calculations for several model reactions in the gas phase that are relevant to the DHFR catalyzed hydride transfer. To this end, we employ G4MP2 and CBS-QB3 ab initio calculations as well as numerous density functional theory methods. Using these results, we develop two specific reaction parameter (SRP) Hamiltonians based on the semiempirical AM1 method. The first generation SRP Hamiltonian does not account for dispersion, while the second generation SRP accounts for dispersion implicitly via the AM1 core-repulsion functions. These SRP semiempirical Hamiltonians are subsequently used in hybrid quantum mechanics/molecular mechanics simulations of the DHFR catalyzed reaction. Finally, kinetic isotope effects are computed using a mass-perturbation-based path-integral approach.