Navrátilová Veronika, Paloncýová Markéta, Berka Karel, Otyepka Michal
Regional Centre of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science, Palacký University Olomouc , tř. 17. listopadu 12, 771 46 Olomouc, Czech Republic.
J Phys Chem B. 2016 Nov 3;120(43):11205-11213. doi: 10.1021/acs.jpcb.6b10108. Epub 2016 Oct 19.
Microsomal cytochrome P450 enzymes (CYPs) are membrane-attached enzymes that play indispensable roles in biotransformations of numerous endogenous and exogenous compounds. Although recent progress in experiments and simulations has allowed many important features of CYP-membrane interactions to be deciphered, many other aspects remain underexplored. Using microsecond-long molecular dynamics simulations, we analyzed interaction of CYP3A4 with bilayers composed of lipids differing in their polar head groups, i.e., phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and phosphatidylglycerol. In the negatively charged lipids, CYP3A4 was immersed more deeply and was more inclined toward the membrane because of favorable electrostatic and hydrogen bonding interactions between the CYP catalytic domain and lipid polar head groups. We showed that electrostatics significantly contributes to positioning and orientation of CYP on the membrane and might contribute to the experimentally observed preferences of individual CYP isoforms to distribute in (dis)ordered membrane microdomains.
微粒体细胞色素P450酶（CYPs）是膜附着酶，在众多内源性和外源性化合物的生物转化中发挥着不可或缺的作用。尽管最近在实验和模拟方面取得的进展使人们得以解读CYP与膜相互作用的许多重要特征，但许多其他方面仍未得到充分探索。我们使用长达微秒级的分子动力学模拟，分析了CYP3A4与由极性头部基团不同的脂质组成的双层膜之间的相互作用，即磷脂酰胆碱、磷脂酰乙醇胺、磷脂酰丝氨酸和磷脂酰甘油。在带负电荷的脂质中，由于CYP催化结构域与脂质极性头部基团之间存在有利的静电和氢键相互作用，CYP3A4被更深入地浸入膜中，并且更倾向于膜。我们表明，静电作用对CYP在膜上的定位和取向有显著贡献，并且可能有助于解释实验观察到的各个CYP同工型在（无序）膜微区中分布的偏好。
