Quantum mechanics-coupled AMBER ff99 compatible heme parameters for the P450 catalytic cycle


Kiumars Shahrokh, kiu@pharm.utah.edu1, Garold S. Yost1, and Thomas E. Cheatham III, tec3@utah.edu2. (1) Department of Pharmacology and Toxicology, University of Utah, 30 South 2000 East Room 201, Salt Lake City, UT 84112, (2) Departments of Medicinal Chemistry and of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, 2000 East, 30 South, Skaggs Hall 201, Salt Lake City, UT 82117
The lack of a consistent set of atomic parameters for the key heme species during the P450 catalytic cycle has limited the accuracy of computational methods for predicting drug metabolism. Our research focuses on elucidating the contribution of electronic, conformational and thermodynamic factors to competing P450-catalyzed reaction mechanisms during the metabolism of tamoxifen -the current drug of choice for the treatment of breast cancer. We present the results of our quantum mechanics calculations for key heme species during the P450 catalytic cycle at the UB3LYP/LACVP level. These results have been further used to develop a consistent set of AMBER ff99-compatible parameters for the P450 catalytic cycle. We will discuss the contribution of these parameters towards the improved accuracy of our combined empirical and computational approach which uses coupled QM-based force field development, flexible docking, and extensive MD in explicit solvent to study the biophysical factors involved in P450-mediated drug metabolism.