Molecular Dynamics of Human Cytochrome P450 2D6 to Investigate E↵ects of Polymorphic Variation on Metabolism of Bufuralol
Sunden, Kyle F.
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Cytochromes P450 are a superfamily of heme-containing enzymes responsible for the metabolism of small molecules. CYP2D6 is responsible for about 15 percent of xenobiotic metabolism in humans. CYP2D6 is also expressed with a high degree of allelic variation, resulting in greatly differed rates of metabolism across individuals. This has implications for the application of medical treatments to patients who express forms of CYP2D6 that metabolize drugs at differing rates. Computational methods were used to gain insights into how individual amino acid substitutions cause changes to the structural stability and plasticity of CYP2D6. Ultimately, the methods are intended as a way to characterize how the observed reaction rates correlate to computational data on a molecular scale. The dynamics of six variants, *1, *53, *34, *2, *17-2, and *17-3, and one mutant, *1-T309A, were studied. The variants possess a variety of substitutions distal and local to the active site that affect enzyme activity. Trends in flexibility and substrate orientation were observed through molecular dynamics (MD) simulations using AMBER14 with AmberTools15. The results show that bufuralol behaves in a similar manner within the active site of the variants, but the enzymes have differences in the surrounding structure. Root-Mean-Squared Deviation and Root-Mean-Squared Fluctuation were used to characterize the differences in enzyme structure. Molecular Dynamics confirmed that the portions that lacked secondary structure, particularly the F-G loop region, were the most flexible residues in all variants. The C-D loop of the two variants that contain the T107I substitution, *17-2 and *17-3, showed increased flexibility compared to *1 with no ligand bound that was greatly diminished in simulations with ligand bound. Principal Component Analysis was used to determine the orientation of the ligand, bufuralol, within the active site and show possible differences. (Support: NIH 1R15GM086767-02 to LLF and NSF ACI-1053575 to XSEDE) iii