title: Development of models for cytochrome P450 2A5 as well as two of its mutants.
abstract: It is known that small changes in the amino acid sequence can change the catalytic activity of cytochromes towards substrates dramatically. With the aim to broaden our knowledge about the structural properties of cytochromes and their relation with substrate specificity a model of CYP2A5 was built by homology modelling based on the crystal structure of CYP2C5. Model stability was evaluated by subjection of the model to a free molecular dynamics simulation in a waterbox under almost physiological conditions using the GROMACS program. The protein folding remains stable over 1.5 ns under these conditions. The modelling procedure was repeated for two mutated forms of CYP2A5 with known differing substrate selectivities towards corticosterone and desoxycorticosterone. A detailed analysis of the models and their behaviour in long running molecular dynamics simulations allows an understanding of the requirements for enzyme activity as well as an explanation of respective experimental data on the molecular level.
authors.affiliation: Department of Pharmacy, Institute of Pharmaceutical Chemistry, Heinrich Heine-University, Düsseldorf, Germany.
authors.forename: G R
authors.initials: GR
authors.lastname: Stahl
authors.forename: H D
authors.initials: HD
authors.lastname: Höltje
mesh_terms: D000595:Amino Acid Sequence; D001189:Aryl Hydrocarbon Hydroxylases / Q000737:chemistry* / Q000235:genetics*; D003345:Corticosterone / Q000378:metabolism; D065637:Cytochrome P-450 CYP2A6; D003900:Desoxycorticosterone / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000737:chemistry* / Q000235:genetics*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010100:Oxygen / Q000737:chemistry; D017354:Point Mutation; D011487:Protein Conformation; D017510:Protein Folding; D013379:Substrate Specificity
chemical_list: D003900:Desoxycorticosterone; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; D065637:Cytochrome P-450 CYP2A6; D010100:Oxygen; D003345:Corticosterone