Program

PO1-13-20

Molecular dynamics studies of the pH-dependent dynamic structure on CYP2D6

[Speaker] Masanori Ootaki:1
[Co-author] Yuki Ohta:1, Yuko Takeba:1, Minoru Watanabe:2, Tsukasa Kobayashi:1, Yuki Nakamura:1, Daiki Watanabe:1, Makoto Yamamoto:3, Taroh Iiri:1, Naoki Matsumoto:1
1:Department of Pharmacology, St. Marianna University School of Medicine, Japan, 2:Institute for Animal Experimentation, St. Marianna University Graduate School of Medicine, Japan, 3:Division of Nephrology and Hypertension, St. Marianna University School of Medicine, Japan

 CYP2D6 affects metabolization of drugs such as antidepressants and opioids, and examination of its mechanism of action is important for understanding drug metabolism. CYP is expressed not only in the liver but also in the small intestine, and is known to affect the first pass effect. Enzymatic reactions are altered depending upon pH, temperature, and other internal conditions of the body, resulting different the liver or small intestine, though difficult to be evaluated. In the previous study, we have reported the possibility that CYP2D6 isolated from the human liver and small intestine may have different activities. In the present study, we used molecular dynamics calculations to investigate the effects of environmental conditions on the activity and stability of CYP2D6 such as pH around the protein.
 AMBER16 was used for molecular dynamics calculations of CYP2D6, and the wild type protein registered in Protein Data Bank was used as the initial structure (PDB ID 3qm4 chain A). In CYP2D6, there are 13 His residues, and His376 is in the proximity of heme iron. When periodic boundary condition were used with these residues differing in the side chain dissociation state (pH6.5, 7.5) to evaluate structural changes in the active center.
 When His was dissociated, changes in the crystal structure were observed for His416, His477, and His478 residues exposed on the surface of CYP2D6; the side chain moved by 1.8 Å. This is presumably because His477 and His488 are adjacent to each other, resulting in a repulsive force when they are at a close proximity. On the other hand, when His376 in the vicinity of the active center was dissociated, the side chain of His376 itself was twisted, resulting in the maximum deviation of about 1 Å with about 60° distortion from the crystal structure. However, virtually no changes from the crystal structure occurred with respect to the heme group. The concluded that structural differences between pH 6.5 and pH 7.5 have little effect on the CYP2D6 activity and stability.


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