TY  - GEN
ID  - heidok24171
N2  - Human cytochrome P450 (CYP) enzymes play an important role in the metabolism of drugs, steroids, fatty acids and xenobiotics. CYPs also catalyze the conversion of some pro-drugs into active drugs. Only about a dozen human CYPs metabolize 70-80% of all drugs. A subset of CYPs is responsible for steroidogenesis, of these CYP17 is a major drug target for prostate cancer therapy. Human CYPs are anchored to the endoplasmic reticulum membrane by their N-terminal transmembrane (TM) helix. However, most crystal structures of CYPs have been resolved after truncating the TM-helix or mutating residues that form contacts with the membrane. Therefore, the structural basis for CYP-membrane interactions and orientation, and the mechanism of substrate entrance into the buried binding pocket and product release is not clearly understood.
 In order to understand the interactions and orientations of CYPs and their degree of penetration into the membrane, I have optimized a multiscale modeling protocol that involves coarse-grained and all-atom molecular dynamics simulations. The protocol was validated by applying it to several drug-metabolizing CYPs (CYP1A1, 1A2, 2C9, 2C19, 3A4) and CYPs involved in steroidogenesis (CYP17, CYP19) in a lipid bilayer. The simulations revealed that the sequence and structural differences in the protein-membrane interface alter the interactions and orientations of CYPs in the membrane. Furthermore, mutations in the TM-helix of CYP17, particularly W2A and E3L, were seen to disrupt the CYP-membrane interactions and in some cases, obstruct the ligand tunnels between the active site and the membrane, which could lower enzyme turnover.  
In conclusion, the optimized multiscale simulation protocol has been used to identify different interactions and orientations adopted by the globular domains of CYPs with the membrane that have implications for CYP function. This protocol is also suitable for studying protein-protein-membrane complexes and proteins in membranes with different lipid compositions.
A1  - Mustafa, Ghulam
UR  - https://archiv.ub.uni-heidelberg.de/volltextserver/24171/
AV  - public
Y1  - 2018///
TI  - Modeling and Simulation of Membrane Proteins to Understand their Structure, Dynamics and Function
CY  - Heidelberg
KW  - Membrane protein interactions
Ligand entrance tunnels
LIPID forcefield
Transmembrane helix mutations
Martini coarse-grained simulation
All-atom simulations
Heme cofactor
ER  -