ACTIVE-SITE MOBILITY INHIBITS REDUCTIVE DEHALOGENATION OF 1,1,1-TRICHLOROETHANE BY CYTOCHROME P450CAM

Recent studies by Wackett and co-workers have shown that cytochrome P4 50cam is capable of reductively dehalogenating hexachloroethane at a s ignificant rate, but that no appreciable dehalogenation of 1,1,1-trich loroethane is observed. A growing body of evidence indicates that diff erences in intrinsic reactivity can not completely explain this observ ation. We therefore explored the possible role of differences in prefe rred binding orientation and in active-site mobility. A detailed analy sis of molecular dynamics trajectories with each of these substrates b ound at the active site of P450cam is presented. While the dynamics an d overall time-average structure calculated for the protein are simila r in the two trajectories, the two substrates behave quite differently . The smaller substrate, 1,1,1-trichloroethane, is significantly more mobile than hexachloroethane and has a preferred orientation in which the substituted carbon is generally far from the heme iron. In contras t, for hexachloroethane, one of the chlorine atoms is nearly always in van der Waals contact with the heme iron, which should favor the init ial electron transfer step.