362
Z. Fu and J. Chen
12. Harris D, Loew G (1993) Determinants of the spin state of the resting state of cytochrome
P450cam. J Am Chem Soc 115(19):8775–8779
13. Kumar D, de Visser SP, Sharma PK, Cohen S, Shaik S (2004) Radical clock substrates, their
C–H hydroxylation mechanism by cytochrome P450, and other reactivity patterns: what does
theory reveal about the clocks’ behavior? J Am Chem Soc 126(6):1907–1920
14. Yoshizawa K, Kamachi T, Shiota Y (2001) A theoretical study of the dynamic behavior
of alkane hydroxylation by a Compound I model of cytochrome P450. J Am Chem Soc
123(40):9806–9816
15. de Visser SP, Kumar D, Cohen S, Shacham R, Shaik S (2004) A predictive pattern of computed barriers for C–H hydroxylation by compound i of cytochrome P450. J Am Chem Soc
126(27):8362–8363
16. Shaik S, Kumar D, de Visser SP (2008) A valence bond modeling of trends in hydrogen
abstraction barriers and transition states of hydroxylation reactions catalyzed by cytochrome
P450 enzymes. J Am Chem Soc 130(31):10128–10140
17. de Visser SP, Ogliaro F, Harris N, Shaik S (2001) Multi-state epoxidation of ethene by
cytochrome P450: a quantum chemical study. J Am Chem Soc 123(13):3037–3047
18. de Visser SP, Ogliaro F, Sharma PK, Shaik S (2002) What factors affect the regioselectivity
of oxidation by cytochrome P450? A DFT study of allylic hydroxylation and double bond
epoxidation in a model reaction. J Am Chem Soc 124(39):11809–11826
19. de Visser SP, Shaik S (2003) A proton-shuttle mechanism mediated by the porphyrin in benzene
hydroxylation by cytochrome P450 enzymes. J Am Chem Soc 125(24):7413–7424
20. Sharma PK, de Visser SP, Shaik S (2003) Can a single oxidant with two spin states masquerade
as two different oxidants? A study of the sulfoxidation mechanism by cytochrome P450. J Am
Chem Soc 125(29):8698–8699
21. van der Kamp MW, Mulholland AJ (2013) Combined quantum mechanics/molecular mechanics (QM/MM) methods in computational enzymology. Biochemistry 52(16):2708–2728
22. Schöneboom JC, Lin H, Reuter N, Thiel W, Cohen S, Ogliaro F, Shaik S (2002) The elusive
oxidant species of cytochrome P450 enzymes: characterization by combined quantum mechanical/molecular mechanical (QM/MM) calculations. J Am Chem Soc 124(27):8142–8151
23. Guallar V, Friesner RA (2004) Cytochrome P450cam enzymatic catalysis cycle: a quantum
mechanics/molecular mechanics study. J Am Chem Soc 126(27):8501–8508
24. Altun A, Guallar V, Friesner RA, Shaik S, Thiel W (2006) The effect of heme environment on
the hydrogen abstraction reaction of camphor in P450cam catalysis: A QM/MM study. J Am
Chem Soc 128(12):3924–3925
25. Ramanan R, Dubey KD, Wang B, Mandal D, Shaik S (2016) Emergence of function in P450proteins: a combined quantum mechanical/molecular mechanical and molecular dynamics
study of the reactive species in the H 2 O 2 -dependent cytochrome p450(sp alpha) and its regioand enantioselective hydroxylation of fatty acids. J Am Chem Soc 138(21):6786–6797
26. Ogliaro F, Cohen S, de Visser SP, Shaik S (2000) Medium polarization and hydrogen bonding
effects on Compound I of cytochrome P450: what kind of a radical is it really? J Am Chem
Soc 122(51):12892–12893
27. Ogliaro F, Harris N, Cohen S, Filatov M, de Visser SP, Shaik S (2000) A model “rebound”
mechanism of hydroxylation by cytochrome P450: stepwise and effectively concerted pathways, and their reactivity patterns. J Am Chem Soc 122(37):8977–8989
28. Kumar D, de Visser SP, Shaik S (2003) How does product isotope effect prove the operation
of a two-state “rebound” mechanism in C–H hydroxylation by cytochrome P450? J Am Chem
Soc 125(43):13024–13025
29. Wang Y, Kumar D, Yang C, Han K, Shaik S (2007) Theoretical study of N-demethylation of
substituted N,N-dimethylanilines by cytochrome P450: the mechanistic significance of kinetic
isotope effect profiles. J Phys Chem B 111(26):7700–7710
30. Li CS, Wu W, Kumar D, Shaik S (2006) Kinetic isotope effect is a sensitive probe of spin state
reactivity in C–H hydroxylation of N,N-dimethylaniline by cytochrome P450. J Am Chem Soc
128(2):394–395
Z. Fu and J. Chen
12. Harris D, Loew G (1993) Determinants of the spin state of the resting state of cytochrome
P450cam. J Am Chem Soc 115(19):8775–8779
13. Kumar D, de Visser SP, Sharma PK, Cohen S, Shaik S (2004) Radical clock substrates, their
C–H hydroxylation mechanism by cytochrome P450, and other reactivity patterns: what does
theory reveal about the clocks’ behavior? J Am Chem Soc 126(6):1907–1920
14. Yoshizawa K, Kamachi T, Shiota Y (2001) A theoretical study of the dynamic behavior
of alkane hydroxylation by a Compound I model of cytochrome P450. J Am Chem Soc
123(40):9806–9816
15. de Visser SP, Kumar D, Cohen S, Shacham R, Shaik S (2004) A predictive pattern of computed barriers for C–H hydroxylation by compound i of cytochrome P450. J Am Chem Soc
126(27):8362–8363
16. Shaik S, Kumar D, de Visser SP (2008) A valence bond modeling of trends in hydrogen
abstraction barriers and transition states of hydroxylation reactions catalyzed by cytochrome
P450 enzymes. J Am Chem Soc 130(31):10128–10140
17. de Visser SP, Ogliaro F, Harris N, Shaik S (2001) Multi-state epoxidation of ethene by
cytochrome P450: a quantum chemical study. J Am Chem Soc 123(13):3037–3047
18. de Visser SP, Ogliaro F, Sharma PK, Shaik S (2002) What factors affect the regioselectivity
of oxidation by cytochrome P450? A DFT study of allylic hydroxylation and double bond
epoxidation in a model reaction. J Am Chem Soc 124(39):11809–11826
19. de Visser SP, Shaik S (2003) A proton-shuttle mechanism mediated by the porphyrin in benzene
hydroxylation by cytochrome P450 enzymes. J Am Chem Soc 125(24):7413–7424
20. Sharma PK, de Visser SP, Shaik S (2003) Can a single oxidant with two spin states masquerade
as two different oxidants? A study of the sulfoxidation mechanism by cytochrome P450. J Am
Chem Soc 125(29):8698–8699
21. van der Kamp MW, Mulholland AJ (2013) Combined quantum mechanics/molecular mechanics (QM/MM) methods in computational enzymology. Biochemistry 52(16):2708–2728
22. Schöneboom JC, Lin H, Reuter N, Thiel W, Cohen S, Ogliaro F, Shaik S (2002) The elusive
oxidant species of cytochrome P450 enzymes: characterization by combined quantum mechanical/molecular mechanical (QM/MM) calculations. J Am Chem Soc 124(27):8142–8151
23. Guallar V, Friesner RA (2004) Cytochrome P450cam enzymatic catalysis cycle: a quantum
mechanics/molecular mechanics study. J Am Chem Soc 126(27):8501–8508
24. Altun A, Guallar V, Friesner RA, Shaik S, Thiel W (2006) The effect of heme environment on
the hydrogen abstraction reaction of camphor in P450cam catalysis: A QM/MM study. J Am
Chem Soc 128(12):3924–3925
25. Ramanan R, Dubey KD, Wang B, Mandal D, Shaik S (2016) Emergence of function in P450proteins: a combined quantum mechanical/molecular mechanical and molecular dynamics
study of the reactive species in the H 2 O 2 -dependent cytochrome p450(sp alpha) and its regioand enantioselective hydroxylation of fatty acids. J Am Chem Soc 138(21):6786–6797
26. Ogliaro F, Cohen S, de Visser SP, Shaik S (2000) Medium polarization and hydrogen bonding
effects on Compound I of cytochrome P450: what kind of a radical is it really? J Am Chem
Soc 122(51):12892–12893
27. Ogliaro F, Harris N, Cohen S, Filatov M, de Visser SP, Shaik S (2000) A model “rebound”
mechanism of hydroxylation by cytochrome P450: stepwise and effectively concerted pathways, and their reactivity patterns. J Am Chem Soc 122(37):8977–8989
28. Kumar D, de Visser SP, Shaik S (2003) How does product isotope effect prove the operation
of a two-state “rebound” mechanism in C–H hydroxylation by cytochrome P450? J Am Chem
Soc 125(43):13024–13025
29. Wang Y, Kumar D, Yang C, Han K, Shaik S (2007) Theoretical study of N-demethylation of
substituted N,N-dimethylanilines by cytochrome P450: the mechanistic significance of kinetic
isotope effect profiles. J Phys Chem B 111(26):7700–7710
30. Li CS, Wu W, Kumar D, Shaik S (2006) Kinetic isotope effect is a sensitive probe of spin state
reactivity in C–H hydroxylation of N,N-dimethylaniline by cytochrome P450. J Am Chem Soc
128(2):394–395