Cytochrome P450 - membrane interactions
Identification of Optimal CYP-membrane Interactions: My postdoctoral research work at molecular and cellular modeling group with Prof. Wade on cytochrome P450 (CYP), a drug metabolizing enzyme and an anticancer drug target, was focused on identifying optimum interactions between CYP protein and bio-membrane using multi-scale (Martini coarse-grained and atomic-resolution) MD simulations. We reported an ab-initio protocol to built and simulate human CYP proteins in its native membrane-bound form to optimize protein-membrane interactions which is an important step of protein-membrane MD simulations (J. Chem. Phys. 2016). The study is particularly important to the research community working on protein-membrane MD simulations.
The study provided important guidelines to build and simulate protein in membrane-bound form when few/no experimental data are available about protein and membrane interactions. In a similar study, we investigated a few differences between human and parasitic CYP51 and proposed to exploit these differences for anti-parasitic drug design against Trypanosoma brucei (BBA Gen. Sub. 2016). Also, we characterized the potential ligand egress routes and mechanisms in T. brucei and human CYP51 enzymes using Random Acceleration Molecular Dynamics (RAMD) simulations. The study demonstrated a mechanism of substrate entrance to the cavity and egress of a metabolite from the CYP, thereby explaining one of the important processes involved in CYP mediated drug metabolism.
Publications:
Xiaofeng Yu, Prajwal Nandekar, Ghulam Mustafa, Vlad Cojocaru, Galina I. Lepesheva, Rebecca C. Wade; Ligand tunnels in T. brucei and human CYP51: Insights for parasite-specific drug design, 2016, Biochimica et Biophysica Acta (BBA) - General Subject, Volume 1860 (1), Part A, Pages 67-78, IF: 4.702
Ghulam Mustafa, Prajwal P Nandekar*, Xiaofeng Yu, Rebecca C Wade; On the application of the MARTINI coarse-grained model to immersion of a protein in a phospholipid bilayer, 2015, The Journal of chemical physics, Volume 143 (24), Pages 12B621_1, IF: 2.965