TY - JOUR
T1 - QM/MM study of mechanisms for compound I formation in the catalytic cycle of cytochrome P450cam
AU - Zheng, Jingjing
AU - Wang, Dongqi
AU - Thiel, Walter
AU - Shaik, Sason
PY - 2006/10/11
Y1 - 2006/10/11
N2 - In the catalytic cycle of cytochrome P450cam, after molecular oxygen binds as a ligand to the heme iron atom to yield a ferrous dioxygen complex, there are fast proton transfers that lead to the formation of the active species, Compound I (Cpd I), which are not well understood because they occur so rapidly. In the present work, the conversion of the ferric hydroperoxo complex (Cpd 0) to Cpd I has been investigated by combined quantum-mechanical/molecular- mechanical (QM/MM) calculations. The residues Asp251 and Glu 366 are considered as proton sources. In mechanism I, a proton is transported to the distal oxygen atom of the hydroperoxo group via a hydrogen bonding network to form protonated Cpd 0 (prot-Cpd0: FeOOH2), followed by heterolytic O-O bond cleavage that generates Cpd I and water. Although a local minimum is found for prot-Cpd0 in the Glu366 channel, it is very high in energy (more than 20 kcal/mol above Cpd 0) and the barriers for its decay are only 3-4 kcal/mol (both toward Cpd 0 and Cpd I). In mechanism II, an initial O-O bond cleavage followed by a concomitant proton and electron transfer yields Cpd I and water. The rate-limiting step in mechanism II is O-O cleavage with a barrier of about 13-14 kcal/mol. According to the QM/MM calculations, the favored low-energy pathway to Cpd I is provided by mechanism II in the Asp251 channel. Cpd 0 and Cpd I are of similar energies, with a slight preference for Cpd I.
AB - In the catalytic cycle of cytochrome P450cam, after molecular oxygen binds as a ligand to the heme iron atom to yield a ferrous dioxygen complex, there are fast proton transfers that lead to the formation of the active species, Compound I (Cpd I), which are not well understood because they occur so rapidly. In the present work, the conversion of the ferric hydroperoxo complex (Cpd 0) to Cpd I has been investigated by combined quantum-mechanical/molecular- mechanical (QM/MM) calculations. The residues Asp251 and Glu 366 are considered as proton sources. In mechanism I, a proton is transported to the distal oxygen atom of the hydroperoxo group via a hydrogen bonding network to form protonated Cpd 0 (prot-Cpd0: FeOOH2), followed by heterolytic O-O bond cleavage that generates Cpd I and water. Although a local minimum is found for prot-Cpd0 in the Glu366 channel, it is very high in energy (more than 20 kcal/mol above Cpd 0) and the barriers for its decay are only 3-4 kcal/mol (both toward Cpd 0 and Cpd I). In mechanism II, an initial O-O bond cleavage followed by a concomitant proton and electron transfer yields Cpd I and water. The rate-limiting step in mechanism II is O-O cleavage with a barrier of about 13-14 kcal/mol. According to the QM/MM calculations, the favored low-energy pathway to Cpd I is provided by mechanism II in the Asp251 channel. Cpd 0 and Cpd I are of similar energies, with a slight preference for Cpd I.
UR - http://www.scopus.com/inward/record.url?scp=33749520822&partnerID=8YFLogxK
U2 - 10.1021/ja063439l
DO - 10.1021/ja063439l
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C2 - 17017800
AN - SCOPUS:33749520822
SN - 0002-7863
VL - 128
SP - 13204
EP - 13215
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 40
ER -