The role of protein plasticity in computational rationalization studies on regioselectivity in testosterone hydroxylation by Cytochrome P450 BM3 mutants

S.B.A. de Beer; L.A.H. van Bergen; K. Keijzer; V. Rea; H. Venkataraman; C. Fonseca Guerra; F.M. Bickelhaupt; N.P.E. Vermeulen; J.N.M. Commandeur; D.P. Geerke

doi:10.2174/138920012798918471

The role of protein plasticity in computational rationalization studies on regioselectivity in testosterone hydroxylation by Cytochrome P450 BM3 mutants

S.B.A. de Beer, L.A.H. van Bergen, K. Keijzer, V. Rea, H. Venkataraman, C. Fonseca Guerra, F.M. Bickelhaupt, N.P.E. Vermeulen, J.N.M. Commandeur, D.P. Geerke

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Abstract

Recently, it was found that mutations in the binding cavity of drug-metabolizing Cytochrome P450 BM3 mutants can result in major changes in regioselectivity in testosterone (TES) hydroxylation. In the current work, we report the intrinsic reactivity of TES' C-H bonds and our attempts to rationalize experimentally observed changes in TES hydroxylation using a protein structure-based in silico approach, by setting up and employing a combined Molecular Dynamics (MD) and ligand docking approach to account for the flexibility and plasticity of BM3 mutants. Using this approach, about 100,000 TES binding poses were obtained per mutant. The predicted regioselectivity in TES hydroxylation by the mutants was found to be in disagreement with experiment. As revealed in a detailed structural analysis of the obtained docking poses, this disagreement is due to limitations in correctly scoring hydrogen-bonding and steric interactions with specific active-site residues, which could explain the experimentally observed trends in regioselectivity in TES hydroxylation. © 2012 Bentham Science Publishers.

Original language	English
Pages (from-to)	155-166
Journal	Current Drug Metabolism
Volume	13
Issue number	2
DOIs	https://doi.org/10.2174/138920012798918471
Publication status	Published - 2012

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de Beer, S. B. A., van Bergen, L. A. H., Keijzer, K., Rea, V., Venkataraman, H., Fonseca Guerra, C., Bickelhaupt, F. M., Vermeulen, N. P. E., Commandeur, J. N. M., & Geerke, D. P. (2012). The role of protein plasticity in computational rationalization studies on regioselectivity in testosterone hydroxylation by Cytochrome P450 BM3 mutants. Current Drug Metabolism, 13(2), 155-166. https://doi.org/10.2174/138920012798918471

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title = "The role of protein plasticity in computational rationalization studies on regioselectivity in testosterone hydroxylation by Cytochrome P450 BM3 mutants",

abstract = "Recently, it was found that mutations in the binding cavity of drug-metabolizing Cytochrome P450 BM3 mutants can result in major changes in regioselectivity in testosterone (TES) hydroxylation. In the current work, we report the intrinsic reactivity of TES' C-H bonds and our attempts to rationalize experimentally observed changes in TES hydroxylation using a protein structure-based in silico approach, by setting up and employing a combined Molecular Dynamics (MD) and ligand docking approach to account for the flexibility and plasticity of BM3 mutants. Using this approach, about 100,000 TES binding poses were obtained per mutant. The predicted regioselectivity in TES hydroxylation by the mutants was found to be in disagreement with experiment. As revealed in a detailed structural analysis of the obtained docking poses, this disagreement is due to limitations in correctly scoring hydrogen-bonding and steric interactions with specific active-site residues, which could explain the experimentally observed trends in regioselectivity in TES hydroxylation. {\textcopyright} 2012 Bentham Science Publishers.",

author = "{de Beer}, S.B.A. and {van Bergen}, L.A.H. and K. Keijzer and V. Rea and H. Venkataraman and {Fonseca Guerra}, C. and F.M. Bickelhaupt and N.P.E. Vermeulen and J.N.M. Commandeur and D.P. Geerke",

year = "2012",

doi = "10.2174/138920012798918471",

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de Beer, SBA, van Bergen, LAH, Keijzer, K, Rea, V, Venkataraman, H, Fonseca Guerra, C , Bickelhaupt, FM , Vermeulen, NPE, Commandeur, JNM & Geerke, DP 2012, 'The role of protein plasticity in computational rationalization studies on regioselectivity in testosterone hydroxylation by Cytochrome P450 BM3 mutants', Current Drug Metabolism, vol. 13, no. 2, pp. 155-166. https://doi.org/10.2174/138920012798918471

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T1 - The role of protein plasticity in computational rationalization studies on regioselectivity in testosterone hydroxylation by Cytochrome P450 BM3 mutants

AU - de Beer, S.B.A.

AU - van Bergen, L.A.H.

AU - Keijzer, K.

AU - Rea, V.

AU - Venkataraman, H.

AU - Fonseca Guerra, C.

AU - Bickelhaupt, F.M.

AU - Vermeulen, N.P.E.

AU - Commandeur, J.N.M.

AU - Geerke, D.P.

PY - 2012

Y1 - 2012

N2 - Recently, it was found that mutations in the binding cavity of drug-metabolizing Cytochrome P450 BM3 mutants can result in major changes in regioselectivity in testosterone (TES) hydroxylation. In the current work, we report the intrinsic reactivity of TES' C-H bonds and our attempts to rationalize experimentally observed changes in TES hydroxylation using a protein structure-based in silico approach, by setting up and employing a combined Molecular Dynamics (MD) and ligand docking approach to account for the flexibility and plasticity of BM3 mutants. Using this approach, about 100,000 TES binding poses were obtained per mutant. The predicted regioselectivity in TES hydroxylation by the mutants was found to be in disagreement with experiment. As revealed in a detailed structural analysis of the obtained docking poses, this disagreement is due to limitations in correctly scoring hydrogen-bonding and steric interactions with specific active-site residues, which could explain the experimentally observed trends in regioselectivity in TES hydroxylation. © 2012 Bentham Science Publishers.

AB - Recently, it was found that mutations in the binding cavity of drug-metabolizing Cytochrome P450 BM3 mutants can result in major changes in regioselectivity in testosterone (TES) hydroxylation. In the current work, we report the intrinsic reactivity of TES' C-H bonds and our attempts to rationalize experimentally observed changes in TES hydroxylation using a protein structure-based in silico approach, by setting up and employing a combined Molecular Dynamics (MD) and ligand docking approach to account for the flexibility and plasticity of BM3 mutants. Using this approach, about 100,000 TES binding poses were obtained per mutant. The predicted regioselectivity in TES hydroxylation by the mutants was found to be in disagreement with experiment. As revealed in a detailed structural analysis of the obtained docking poses, this disagreement is due to limitations in correctly scoring hydrogen-bonding and steric interactions with specific active-site residues, which could explain the experimentally observed trends in regioselectivity in TES hydroxylation. © 2012 Bentham Science Publishers.

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DO - 10.2174/138920012798918471

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VL - 13

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JO - Current Drug Metabolism

JF - Current Drug Metabolism

IS - 2

ER -

The role of protein plasticity in computational rationalization studies on regioselectivity in testosterone hydroxylation by Cytochrome P450 BM3 mutants

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