ArticlePhysical chemistry chemical physics : PCCP2016
Lipid molecules can induce an opening of membrane-facing tunnels in cytochrome P450 1A2.
Article in Physical chemistry chemical physics : PCCP, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 20 citations in OpenAlex.
- From closed to open: three dynamic states of membrane-bound cytochrome P450 3A4.Journal of computer-aided molecular design · 2025Article
- Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design.Pharmaceuticals (Basel, Switzerland) · 2021Review
- Spontaneous Ligand Access Events to Membrane-Bound Cytochrome P450 2D6 Sampled at Atomic Resolution.Scientific reports · 2019Article
- Characterization of Lipid-Protein Interactions and Lipid-Mediated Modulation of Membrane Protein Function through Molecular Simulation.Chemical reviews · 2019Review
- Multiscale Simulations of Biological Membranes: The Challenge To Understand Biological Phenomena in a Living Substance.Chemical reviews · 2019Article
- Ligand Access Channels in Cytochrome P450 Enzymes: A Review.International journal of molecular sciences · 2018Review
- Cytochrome-P450-Induced Ordering of Microsomal Membranes Modulates Affinity for Drugs.Angewandte Chemie (International ed. in English) · 2018Article
- Plasma membrane association facilitates conformational changes in the Marburg virus protein VP40 dimer.RSC advances · 2017Article
- The catalytic function of cytochrome P450 is entwined with its membrane-bound nature.F1000Research · 2017Review
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Authors and funding
3 authors at 2 institutions in 2 countries.
Funding
Abstract
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.
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