Compound I in heme thiolate enzymes: a comparative QM/MM study.
This study directly compares the active species of heme enzymes, so-called Compound I (Cpd I), across the heme-thiolate enzyme family. Thus, sixty-four different Cpd I structures are calculated by hybrid quantum mechanical/molecular mechanical (QM/MM) methods using four different cysteine-ligated heme enzymes (P450(cam), the mutant P450(cam)-L358P, CPO and NOS) with varying QM region sizes in two multiplicities each. The overall result is that these Cpd I species are similar to each other with regard to many characteristic features. Hence, using the more stable CPO Cpd I as a model for P450 Cpd I in experiments should be a reasonable approach. However, systematic differences were also observed, and it is shown that NOS stands out in most comparisons. By analyzing the electrical field generated by the enzyme on the QM region, one can see that (a) the protein exerts a large influence and modifies all the Cpd I species compared with the gas-phase situation and (b) in NOS this field is approximately planar to the heme plane, whereas it is approximately perpendicular in the other enzymes, explaining the deviating results on NOS. The calculations on the P450(cam) mutant L358P show that the effects of removing the hydrogen bond between the heme sulfur and L358 are small at the Cpd I stage. Finally, Mossbauer parameters are calculated for the different Cpd I species, enabling future comparisons with experiments. These results are discussed in the broader context of recent findings of Cpd I species that exhibit large variations in the electronic structure due to the presence of the substrate.
Cho
Kyung-Bin
KB
Department of Organic Chemistry and The Lise Meitner-Minerva Center for Computational Quantum Chemistry, The Hebrew University of Jerusalem, 91904 Jerusalem, Israel.
Hirao
Hajime
H
Chen
Hui
H
Carvajal
Maria Angels
MA
Cohen
Shimrit
S
Derat
Etienne
E
Thiel
Walter
W
Shaik
Sason
S
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D003545:Cysteine / Q000737:chemistry; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D005973:Glutamine / Q000737:chemistry; D006418:Heme / Q000378:metabolism*; D006860:Hydrogen Bonding; D007700:Kinetics; D008958:Models, Molecular; D011188:Potassium / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D011789:Quantum Theory; D015204:Spectroscopy, Mossbauer
D005973:Glutamine; D006418:Heme; D003577:Cytochrome P-450 Enzyme System; D003545:Cysteine; D011188:Potassium