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

Xiaofeng Yu, Daria B. Kokh, Prajwal Nandekar, Ghulam Mustafa, Stefan Richter () and Rebecca C. Wade ()
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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

A chapter in High Performance Computing in Science and Engineering ’15, 2016, pp 255-264 from Springer

Abstract: 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.

Keywords: Nicotinamide Adenine Dinucleotide Phosphate; Flavin Adenine Dinucleotide; Nicotinamide Adenine Dinucleotide Phosphate; Cytochrome P450 Reductase; Redox Partner (search for similar items in EconPapers)
Date: 2016
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DOI: 10.1007/978-3-319-24633-8_17

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