Lipid molecules can induce an opening of membrane-facing tunnels in cytochrome P450 1A2.
Lipid molecules can induce an opening of membrane-facing tunnels in cytochrome P450 1A2.
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DOI：
10.1039/c6cp03692a
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发表时间：
2016-11-09
期刊：
影响因子：
--
通讯作者：
Martínek V
中科院分区：
文献类型：
--
作者：
Jeřábek P;Florián J;Martínek V
细胞色素P450 1A 2（P450 1A 2，CYP 1A 2）是一种膜结合酶，可氧化多种疏水底物。使用多尺度计算方法，包括粗粒度和全原子分子动力学的结构和动力学的催化和跨膜（TM）域的这种酶在膜/水环境中进行了研究。从含有TM或可溶性结构域的系统自发自组装开始，将其浸入随机的二月桂酰磷脂酰胆碱（DLPC）/水混合物中，形成各自的膜结合形式，我们重建了全长P450的膜结合结构1A 2。该结构包括跨膜的TM螺旋，同时通过短的柔性环连接到催化结构域。此外，在该模型中，TM螺旋的上部直接与催化结构域的保守且高度疏水的N-末端富含脯氨酸的区段相互作用;该区段和FG环浸没在膜中，而催化结构域的剩余部分保持暴露于水溶液。催化结构域的浅膜浸没似乎诱导磷脂的相对完整层中的凹陷，这可能有助于稳定催化结构域正下方的TM螺旋的位置。催化结构域的部分浸没还允许酶底物通过全长P450 1A 2中的几个面向溶剂和膜的隧道从水溶液或磷脂环境进入活性位点。计算的隧道动力学表明，当DLPC分子自发地渗透到面向膜的隧道2d时，面向膜的隧道的打开概率显著增强。通过线性相互作用能（LIE）近似评估了脂质渗透过程的能量学，并发现其在物理上是可行的。
Cytochrome P450 1A2 (P450 1A2, CYP1A2) is a membrane-bound enzyme that oxidizes a broad range of hydrophobic substrates. The structure and dynamics of both the catalytic and trans-membrane (TM) domains of this enzyme in the membrane/water environment were investigated using a multiscale computational approach, including coarse-grained and all-atom molecular dynamics. Starting from the spontaneous self-assembly of the system containing the TM or soluble domain immersed in randomized dilauroyl phosphatidylcholine (DLPC)/water mixture into their respective membrane-bound forms, we reconstituted the membrane-bound structure of the full-length P450 1A2. This structure includes a TM helix that spans the membrane, while being connected to the catalytic domain by a short flexible loop. Furthermore, in this model, the upper part of the TM helix interacts directly with a conserved and highly hydrophobic N-terminal proline-rich segment of the catalytic domain; this segment and the FG loop are immersed in the membrane, whereas the remaining portion of the catalytic domain remain exposed to the aqueous solution. The shallow membrane immersion of the catalytic domain appears to induce a depression in the opposite intact layer of the phospholipids, which may help in stabilizing the position of the TM helix directly beneath the catalytic domain. The partial immersion of the catalytic domain also allows for the enzyme substrates to enter the active site from either aqueous solution or phospholipid environments via several solvent- and membrane-facing tunnels in the full-length P450 1A2. The calculated tunnel dynamics indicated that the opening probability of the membrane-facing tunnels is significantly enhanced when a DLPC molecule spontaneously penetrates into the membrane-facing tunnel 2d. The energetics of the lipid penetration process were assessed by the linear interaction energy (LIE) approximation, and found to be thermodynamically feasible.
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DOI：
10.1073/pnas.89.22.10915
发表时间：
1992-11-15
影响因子：
11.1
作者：
HENIKOFF, S;HENIKOFF, JG
通讯作者：
HENIKOFF, JG
DOI：
10.1021/jp9064246
发表时间：
2010-03-04
期刊：
The journal of physical chemistry. B
影响因子：
--
作者：
Bren U;Lah J;Bren M;Martínek V;Florián J
通讯作者：
Florián J
DOI：
10.1073/pnas.0811065106
发表时间：
2009-03-24
影响因子：
11.1
作者：
Dror, Ron O.;Arlow, Daniel H.;Shaw, David E.
通讯作者：
Shaw, David E.
影响因子：
15
作者：
Baylon, Javier L.;Lenov, Ivan L.;Sligar, Stephen G.;Tajkhorshid, Emad
通讯作者：
Tajkhorshid, Emad
影响因子：
4.1
作者：
Jerabek, Petr;Florian, Jan;Martinek, Vaclav
通讯作者：
Martinek, Vaclav