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Dynathor: Dynamics of the Complex of Cytochrome P450 and Cytochrome P450 Reductase in a Phospholipid Bilayer

In: High Performance Computing in Science and Engineering ’15

Author

Listed:
  • Xiaofeng Yu

    (HITS gGmbH)

  • Daria B. Kokh

    (HITS gGmbH)

  • Prajwal Nandekar

    (HITS gGmbH)

  • Ghulam Mustafa

    (HITS gGmbH)

  • Stefan Richter

    (HITS gGmbH)

  • Rebecca C. Wade

    (HITS gGmbH
    Heidelberg University, Center for Molecular Biology (ZMBH), DKFZ-ZMBH Alliance
    Heidelberg University, Interdisciplinary Center for Scientific Computing (IWR))

Abstract

The Dynathor project aims at understanding the interaction of cytochrome P450 (CYP, P450) enzymes and their redox partner, cytochrome P450 reductase (CPR), in a phospholipid bilayer. Through simulation studies on the HLRS CRAY systems (initially XE6, later on XC40), we investigated the interactions of models of membrane-bound P450s (CYP51 and CYP1A1) and CPR. A model of membrane-bound T. brucei CYP51 and the human CPR was successfully built and simulated for 217.5 ns. A model of human CYP1A1 and the human CPR in a phospholipid bilayer was also built and is being simulated. These models can be used as starting points to understand the selectivity of the interactions of CYPs with CPR in the native membrane-bound forms, and thus may aid drug discovery projects. Furthermore, we evaluated the method of Random Acceleration Molecular Dynamics (RAMD) for use in calculating relative residence times of proteins with small molecules. This would allow the computation of relative off rates for drug molecules. As a small model system for this evaluation, we use the N-terminal domain of human heat shock protein 90 (HSP90) and a set of different ligands. The obtained RAMD simulated residence times show a clear correlation with experimental values.

Suggested Citation

  • Xiaofeng Yu & Daria B. Kokh & Prajwal Nandekar & Ghulam Mustafa & Stefan Richter & Rebecca C. Wade, 2016. "Dynathor: Dynamics of the Complex of Cytochrome P450 and Cytochrome P450 Reductase in a Phospholipid Bilayer," Springer Books, in: Wolfgang E. Nagel & Dietmar H. Kröner & Michael M. Resch (ed.), High Performance Computing in Science and Engineering ’15, edition 1, pages 255-264, Springer.
    • Handle: RePEc:spr:sprchp:978-3-319-24633-8_17
    DOI: 10.1007/978-3-319-24633-8_17
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