Lipid molecules can induce an opening of membrane-facing tunnels in cytochrome P450 1A2

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11310%2F16%3A10330482" target="_blank" >RIV/00216208:11310/16:10330482 - isvavai.cz</a>

Result on the web

<a href="http://dx.doi.org/10.1039/c6cp03692a" target="_blank" >http://dx.doi.org/10.1039/c6cp03692a</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1039/c6cp03692a" target="_blank" >10.1039/c6cp03692a</a>

Result language

angličtina

Original language name

Lipid molecules can induce an opening of membrane-facing tunnels in cytochrome P450 1A2

Original language description

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 remains exposed to aqueous solution. The shallow membrane immersion of the catalytic domain induces a depression in the opposite intact layer of the phospholipids. This structural effect 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 environment 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.

Czech name

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Czech description

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Type

J_x - Unclassified - Peer-reviewed scientific article (Jimp, Jsc and Jost)

CEP classification

CF - Physical chemistry and theoretical chemistry

OECD FORD branch

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Project

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Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2016

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Physical Chemistry Chemical Physics

ISSN

1463-9076

e-ISSN

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Volume of the periodical

18

Issue of the periodical within the volume

44

Country of publishing house

GB - UNITED KINGDOM

Number of pages

13

Pages from-to

30344-30356

UT code for WoS article

000388492900014

EID of the result in the Scopus database

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