Investigation of substrate recognition for cytochrome P450 1A2 mediated by water molecules using docking and molecular dynamics simulations

J Mol Graph Model. 2017 Jun:74:326-336. doi: 10.1016/j.jmgm.2017.04.006. Epub 2017 Apr 13.

Abstract

The role of water molecules in the active site of cytochrome P450 1A2 (CYP1A2) was investigated using an explicit water model to simulate biological environments. Moreover, differences in ligand recognition between the inhibitor α-naphthoflavone (ANF) and the substrate 7-ethoxyresorufin (7ER) in the CYP1A2 complex were examined. More than 200-ns molecular dynamics (MD) simulations were performed for each complex structure of CYP1A2. In the complex structure with 7ER obtained after MD simulation, some water molecules existed in the active site and formed hydrogen bonds between 7ER and some residues. However, in the complex structure with ANF, the hydrogen bond network differed. These results suggest that CYP1A2 requires water molecules in its active site for substrate recognition. The observed differences in the hydrogen bond network in the complex with ANF or 7ER may be due to the fact that ANF is an inhibitor.

Keywords: CYP1A2; Docking; Ligand recognition; Molecular dynamics; Water.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzoflavones / chemistry
  • Catalytic Domain
  • Cytochrome P-450 CYP1A2 / chemistry*
  • Cytochrome P-450 CYP1A2 Inhibitors / chemistry
  • Humans
  • Hydrogen Bonding
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Oxazines / chemistry
  • Protein Binding
  • Protein Conformation, alpha-Helical
  • Substrate Specificity
  • Water / chemistry*

Substances

  • Benzoflavones
  • Cytochrome P-450 CYP1A2 Inhibitors
  • Oxazines
  • Water
  • ethoxyresorufin
  • alpha-naphthoflavone
  • CYP1A2 protein, human
  • Cytochrome P-450 CYP1A2