de Groot M J, Havenith R W, Vinkers H M, Zwaans R, Vermeulen N P, van Lenthe J H
Leiden/Amsterdam Center for Drug Research (LACDR), Vrije Universiteit, The Netherlands.
J Comput Aided Mol Des. 1998 Mar;12(2):183-93. doi: 10.1023/a:1007971918536.
Geometry optimizations for several spin states of the iron(III)-S-methyl- porphyrin complex, the iron (III)-oxo-S-methyl-porphyrin complex and the respective anions were performed in order to examine models for intermediates in the oxidative cycle of cytochrome P450. The aim of this study was to obtain insights into the ground states of the intermediates of this catalytic cycle and to use the ab initio calculated geometries and charge distributions to suggest better and more realistic parameters for forcefields which are generally used for modeling P450s. The results indicate that the ground states of both the iron(III)-S-methyl-porphyrin complex and the iron(III)-oxo-S-methyl-porphyrin complex are sextet spin states (high spin). The ground states of the anions of both complexes are probably quintet spin states. The fact that experimentally a shift from low spin to high spin is observed upon binding of the substrate suggests that the ab initio calculations for the iron(III)-S-methyl-porphyrin complex in vacuum give a correct representation of the (hydrophobic) substrate-bound state of the active site of P450. The ab initio geometries of the iron-porphyrin complexes are very similar to the experimentally observed geometries, except for the longer iron-sulfur bond in ab initio calculations, which is probably caused by the omission of polarization functions on the sulfur atom during the geometry optimization. The charge distribution in all ab initio calculated complexes can be described by a series of concentric rings of alternating charge, thus allowing a relatively large positive charge on the iron atom. The commonly used forcefields generally underestimate the charge differences between the iron atom and the different parts of the porphyrin moiety or ignore the charges completely. Although forcefield calculations can reproduce the experimental geometry of iron-porphyrin moieties, extension of the forcefields with charges obtained from ab initio calculations should give a better description of the heme moiety in protein modeling and docking experiments.
对铁（III）-S-甲基卟啉配合物、铁（III）-氧代-S-甲基卟啉配合物及其各自阴离子的几种自旋态进行了几何优化，以研究细胞色素P450氧化循环中中间体的模型。本研究的目的是深入了解该催化循环中间体的基态，并利用从头算计算的几何结构和电荷分布，为通常用于模拟细胞色素P450的力场提出更好、更现实的参数。结果表明，铁（III）-S-甲基卟啉配合物和铁（III）-氧代-S-甲基卟啉配合物的基态均为六重态自旋态（高自旋）。两种配合物阴离子的基态可能是五重态自旋态。实验观察到底物结合后从低自旋向高自旋的转变，这一事实表明，真空中铁（III）-S-甲基卟啉配合物的从头算计算正确地反映了细胞色素P450活性位点的（疏水）底物结合状态。铁卟啉配合物的从头算几何结构与实验观察到的几何结构非常相似，只是从头算计算中铁-硫键较长，这可能是由于几何优化过程中硫原子上极化函数的遗漏所致。所有从头算计算配合物中的电荷分布都可以用一系列交替电荷的同心环来描述，从而使铁原子上带有相对较大的正电荷。常用的力场通常低估了铁原子与卟啉部分不同部位之间的电荷差异，或者完全忽略了电荷。虽然力场计算可以重现铁卟啉部分的实验几何结构，但用从头算计算得到的电荷扩展力场，应该能在蛋白质建模和对接实验中更好地描述血红素部分。
