TY - JOUR
T1 - Will P450cam hydroxylate or desaturate alkanes? QM and QM/MM studies
AU - Lai, Wenzhen
AU - Chen, Hui
AU - Cohen, Shimrit
AU - Shaik, Sason
PY - 2011/9/1
Y1 - 2011/9/1
N2 - The hydroxylation versus desaturation for the enzyme P450cam is addressed by comparing the reactivity of the active species Por •+Fe(IV)=O (Cpd I) toward cyclohexane (CH), camphor (CAM), and cyclohexene (CHE). The quantum mechanics (QM)-only calculations, which reveal protein-free trends, show mixed and nonselective hydroxylation/desaturation activities, branching from the PorFe(IV)OH/R• intermediates. By contrast, the quantum mechanics/molecular mechanics (QM/MM) results with CAM and CHE show exclusive alcohol formation. Two distinct modes by which the protein controls the hydroxylation/desaturation selectivity were identified: (a) with the native substrate CAM, the tight binding site of the P450cam protein prevents the second hydrogen abstraction and leads to exclusive C5-H hydroxylation, and (b) with the freely tumbling CHE, the protein stabilizes the polarizable electromers, Por•+Fe(III)OH/R•, which possess intrinsic hydroxylase preference. The latter mechanism is common for substrates that are not tightly bound. It is a unique mechanism to P450 Cpd I, which possesses the Por•+Fe(III)OH electromers that dominate the in-protein reactivity. This is contrasted with nonheme enzymes, which lack such electromers.
AB - The hydroxylation versus desaturation for the enzyme P450cam is addressed by comparing the reactivity of the active species Por •+Fe(IV)=O (Cpd I) toward cyclohexane (CH), camphor (CAM), and cyclohexene (CHE). The quantum mechanics (QM)-only calculations, which reveal protein-free trends, show mixed and nonselective hydroxylation/desaturation activities, branching from the PorFe(IV)OH/R• intermediates. By contrast, the quantum mechanics/molecular mechanics (QM/MM) results with CAM and CHE show exclusive alcohol formation. Two distinct modes by which the protein controls the hydroxylation/desaturation selectivity were identified: (a) with the native substrate CAM, the tight binding site of the P450cam protein prevents the second hydrogen abstraction and leads to exclusive C5-H hydroxylation, and (b) with the freely tumbling CHE, the protein stabilizes the polarizable electromers, Por•+Fe(III)OH/R•, which possess intrinsic hydroxylase preference. The latter mechanism is common for substrates that are not tightly bound. It is a unique mechanism to P450 Cpd I, which possesses the Por•+Fe(III)OH electromers that dominate the in-protein reactivity. This is contrasted with nonheme enzymes, which lack such electromers.
KW - Biophysical Chemistry
UR - http://www.scopus.com/inward/record.url?scp=80052377959&partnerID=8YFLogxK
U2 - 10.1021/jz2007534
DO - 10.1021/jz2007534
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AN - SCOPUS:80052377959
SN - 1948-7185
VL - 2
SP - 2229
EP - 2235
JO - Journal of Physical Chemistry Letters
JF - Journal of Physical Chemistry Letters
IS - 17
ER -