Premium
Molecular Dynamics and Distance‐from‐Average‐Structure Characteristics of Human Cytochrome CYP2D6
Author(s) -
Colwell Quinton E,
Furge Laura
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.920.3
Subject(s) - molecular dynamics , protein dynamics , chemistry , dynamics (music) , protein structure , biological system , ligand (biochemistry) , biophysics , computational biology , chemical physics , stereochemistry , computational chemistry , biology , physics , biochemistry , receptor , acoustics
CYP2D6 is a major enzyme involved in metabolism of at least 10% of all chemicals including ~12% of pharmaceutical drugs. Understanding of how CYP2D6, and CYPs in general, are able to metabolize such a wide‐range of chemicals despite having a buried active site is partly achieved through understanding the motion of structural regions of the protein relative to one another. However, these conformational dynamics of CYP2D6 are poorly defined in part because structure‐determining techniques (e.g. X‐ray crystallography) are limited to a single conformation per protein crystal structure. The current study uses molecular dynamics in conjunction with analytical methods to overcome this limitation. In particular, distance‐from‐average‐structure measurements were made as a means to understanding the conformational dynamics of ligand unbound structures of CYP2D6 in a dilute, aqueous, simulated in vitro environment. Our results show that the protein conformation is constantly changing in statistically significant ways that support regional movements and an overall “breathing” motion of the protein that may allow for ligand movement to and from the active site. Also, specific secondary structural elements were found to have greater ranges in motion than others. These differences followed the commonsensical trend of loop regions being more dynamic than helical regions, although there was significant variability between similar structural elements. Furthermore, significant intra‐regional variability in the ranges of motion existed for all structural elements. Though more analyses will need to be done to understand the significance of these dynamic differences, overall the conclusions from the analysis support the validity of our molecular dynamic simulations approach. Support or Funding Information Support: NIH 1R15‐GM086767‐02 and the F. W. and Elsie L. Heyl, Roger F. and Harried G. Varney, and Hutchcroft Endowments of Kalamazoo College.