Cytochrome P450 1A2 (CYP1A2), one of the major drug-metabolizing enzymes among CYPs, has many variant alleles. The genetic polymorphism of CYP1A2 is thought to cause individual differences in the pharmacokinetics of medicines. CYP1A2.8 (the Arg456His mutant), a CYP1A2 variant, has decreased enzymatic activity. In our previous work, to understand why the Arg456His mutant lost its enzymatic activity, we constructed an Arg456His mutant with the hydrogen on the epsilon nitrogen of the histidine (HIE) and performed a 300-ns MD simulation. After the MD simulation, the Arg456His mutant with HIE showed large differences in static structure and flexibility compared with the wild type, which would cause the decreased activity. In the work described here, we constructed an additional Arg456His mutant with positively charged histidine and performed a 300-ns MD simulation to consider the effect of the protonation state of the histidine. Comparing these two Arg456His mutants revealed differences in their static structures, flexibilities, and interactions, suggesting that the protonation state of the His456 residue has a considerable influence on the physiological properties of CYPs. Our results indicate that the Arg456His mutation causes the CYP1A2 structure to unfold regardless of the protonation state of His456.
|Journal||Journal of Physics: Conference Series|
|Publication status||Published - 2018 Dec 24|
|Event||29th IUPAP Conference on Computational Physics, CCP 2017 - , France|
Duration: 2017 Jul 9 → 2017 Jul 13
ASJC Scopus subject areas
- Physics and Astronomy(all)