Understanding the Mechanism of Human P450 CYP1A2 Using Coupled Quantum-Classical Simulations in a Dynamical Environment

Draeger, E W ; Bennion, B ; Gygi, F ; Lightstone, F

Lawrence Livermore National Laboratory

关键词: 99 General And Miscellaneous//Mathematics, Computing, And Information Science;    Carcinogens;    Enzymes;    Oxygen;    59 Basic Biological Sciences;   

DOI  :  10.2172/899113
RP-ID  :  UCRL-TR-219003
RP-ID  :  W-7405-ENG-48
RP-ID  :  899113

美国|英语

来源: UNT Digital Library

【 摘 要 】

The reaction mechanism of the human P450 CYP1A2 enzyme plays a fundamental role in understanding the effects of environmental carcinogens and mutagens on humans. Despite extensive experimental research on this enzyme system, key questions regarding its catalytic cycle and oxygen activation mechanism remain unanswered. In order to elucidate the reaction mechanism in human P450, new computational methods are needed to accurately represent this system. To enable us to perform computational simulations of unprecedented accuracy on these systems, we developed a dynamic quantum-classical (QM/MM) hybrid method, in which ab initio molecular dynamics are coupled with classical molecular mechanics. This will provide the accuracy needed to address such a complex, large biological system in a fully dynamic environment. We also present detailed calculations of the P450 active site, including the relative charge transfer between iron porphine and tetraphenyl porphyrin.