Cytochrome P450 is a vital enzyme in oxidative biotransformations, responsible for the detoxification of biological systems and for the synthesis of sex hormones. Recent experimental results demonstrate that, despite previous reports, 4] the active species of the enzyme, compound I (Cpd I, 1; Scheme 1), might have never been detected since it does not seem to accumulate during the catalytic cycle even at low temperature. To date, the only characterized Cpd I of a cysteinate enzyme belongs to chloroperoxidase (CPO). However, here too the geometry of the species is unknown, and the precise identity of the ground state is still debated. 6] Thus, a key species of one of the most important enzymes of biological systems is known to exist, but eludes detection. We present here theoretical calculations of the so far most extensive and most realistic Cpd I model, 8] with an account of the interaction types exerted by the apoprotein environment. We assign the ground state of Cpd I (1) as A2u, thereby settling previous theoretical disagreements and hopefully contributing toward an eventual resolution of the experimental controversy. The calculations project the unusual nature of this Cpd I that behaves as a chameleon species by adopting its electronic and geometric features to the protein environment to which it has to accomodate. Our benchmark system 2 (Scheme 1) involves octamethyl porphyrin and an axial cysteinato ligand. From an electronic point of view, methyl substituents are good representations of the side chains in 1, while avoiding complications due to internal rotations of the long side chains. Noncovalent interactions revealed by mimetic systems, mutation studies, and X-ray crystal structures of P450 enzymes 11] were taken into account as follows: a) Embedding of 2 in a polarizing medium of a low dielectric constant (e5.7) serves to mimic the effect of polarization by the dipoles of the protein pocket near Cys 357 (using the numbering system in P450cam). b) An internal NH ́ ́ ́ S [1] S. R. Adams, R. Y. Tsien, Annu. Rev. Physiol. 1993, 35, 755 ± 784. [2] D. W. J. Cruickshank, J. R. Helliwell, L. N. Johnson, Time-Resolved Macromolecular Crystallography, Oxford University Press, Oxford, 1992. [3] I. Schlichting, Acc. Chem. Res. 2000, 33, 532 ± 538; M. H. B. Stowell, T. M. McPhillips, D. C. Rees, S. M. Soltis, E. Abresch, G. Feher, Science 1997, 276, 812 ± 816; B. Perman, V. Srajer, Z. Ren, T. Y. Teng, C. Pradervand, T. Ursby, D. Bourgeois, F. Schotte, M. Wulff, R. Kort, K. Hellingwerf, K. Moffat, Science 1998, 279, 1946 ± 1950. [4] I. Schlichting, S. C. Almo, G. Rapp, K. Wilson, K. Petratos, A. Lentfer, A. Wittinghofer, W. Kabsch, E. F. Pai, G. Petsko, R. S. Goody, Nature 1990, 345, 309 ± 315; B. L. Stoddard, P. Koenigs, N. Porter, K. Petratos, G. A. Petsko, D. Ringe, Proc. Natl. Acad. Sci. USA 1991, 88, 5503 ± 5507; B. L. Stoddard, B. E. Cohen, M. Brubaker, A. D. Mesecar, D. E. Koshland, Nat. Struct. Biol. 1998, 5, 891 ± 897. [5] J. M. Bolduc, D. H. Dyer, W. G. Scott, P. Singer, R. M. Sweet, D. E. Koshland, B. L. Stoddard, Science 1995, 268, 1312 ± 1318. [6] J. Hajdu, I. Andersson, Annu. Rev. Biophys. Biomol. Struct. 1993, 22, 467 ± 498. [7] G. Rapp, Methods Enzymol. 1998, 291, 202 ± 222. [8] I. Schlichting, R. S. Goody, Methods Enzymol. 1997, 277, 467 ± 490; M. Weik, R. B. G. Ravelli, G. Kryger, S. McSweeney, M. L. Raves, M. Harel, P. Gros, I. Silman, J. Kroon, J. L. Sussman, Proc. Natl. Acad. Sci. USA 2000, 97, 623 ± 628. [9] K. Moffat, R. Henderson, Curr. Opin. Struct. Biol. 1995, 5, 656 ± 663. [10] A. J. Scheidig, C. Burmester, R. S. Goody, Structure 1999, 7, 1311 ± 1324. [11] T. Y. Teng, K. Moffat, J. Appl. Crystallogr. 1998, 31, 252 ± 257. [12] L. Peng, I. Silman, J. L. Sussman, M. Goeldner, Biochemistry 1996, 35, 10 854 ± 10 861; L. Peng, M. Goeldner, Methods Enzymol. 1998, 291, 265 ± 278. [13] A. Ostermann, R. Waschipky, F. G. Parak, G. U. Nienhaus, Nature 2000, 404, 205 ± 208. [14] L. Peng, F. Nachon, J. Wirz, M. Goeldner, Angew. Chem. 1998, 110, 2838 ± 2840; Angew. Chem. Int. Ed. 1998, 37, 2691 ± 2693. [15] J. M. Walker, G. P. Reid, J. A. McCray, D. R. Trentham, J. Am. Chem. Soc. 1988, 110, 7170 ± 7177. [16] I. R. Dunkin, J. Gebicki, M. Kiszka, D. Sanin-Leira, Spectrochim. Acta Part A 1997, 53, 2553 ± 2557. [17] J. L. Sussman, M. Harel, F. Frolow, C. Oefner, A. Goldman, L. Toker, I. Silman, Science 1991, 253, 872 ± 879. [18] G. Koellner, M. Weik, A. Specht, L. Peng, M. Harel, D. Bourgeois, I. Silman, J. Kroon, M. Goeldner, J. Sussman, unpublished results. [19] T. Ursby, M. Weik, E. Fioravanti, M. Delarue, M. Goeldner, D. Bourgeois, unpublished results.