The regiospecificities of the hydroxylations of d-camphor, d-camphane, d-thiocamphor, and d- and l-norcamphor have been predicted by employing geometric criteria obtained from molecular dynamic simulations of enzyme-substrate interactions in conjunction with the thermodynamic criteria of relative radical energetics derived from nb initio and semiempirical quantum mechanics. Molecular dynamic simulations were performed using the Amber 4.0 suite of programs with modified Lennard-Jones 6-12 parameters and explicit inclusion of all atoms within a 16 Angstrom "belly" region surrounding the reactive ferryl oxygen center. The predictions were in good agreement with experiment for the three substrates for which hydroxylation data are available for resolved enantiomers. Specifically, camphor hydroxylation is predicted to be completely regiospecific (100% at C-5). Camphane, which cannot hydrogen bond to the enzyme, is found to be hydroxylated 90% at C-5, 9% at C-6, and 1% at C-3. Thiocamphor hydroxylation is predicted to be less regiospecific (85% at C-5 and 15% at C-6) than camphor starting from an orientation similar to that of camphor in the P450(cam) binding site. The predicted regioselectivities for all three analogs are in excellent agreement with experimental results. Regiospecificities obtained for d- and l-norcamphor are predictions that remain to be verified. They are not directly comparable with experimental results because hydroxylation products have been determined only for the racematic substrate. The reliability of the constrained protein ("belly") model used was tested for camphor and camphane by performing full protein simulations as well as constrained simulations for these two substrates. The results of both simulations led to comparable predictions of regiospecificity of substrate hydroxylation. These results illustrate the utility of an approximate model of cytochrome P450(cam) that confines unconstrained dynamic motion to a region around the binding site in making accurate predictions of regiospecificity and stereoselectivity of P450(cam) hydroxylation for substrates of moderate size.