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- Li, Junhao, 1989-, et al.
(författare)
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Dissecting the Structural Plasticity and Dynamics of Cytochrome P450 2B4 by Molecular Dynamics Simulations
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The plasticity of cytochrome P450 enzymes (P450s) is known to contribute significantly to their catalytic capacity of metabolizing various substrates. Although numerous studies have been performed, factors governing the plasticity and dynamics of P450s are still not fully understood. In this study, taking CYP2B4 as an example, we dissect the protein plasticity and dynamics in different environments. CYP2B4 is featured by a high degree of plasticity that exhibits open, closed, and intermediate states. By analyzing the CYP2B4 crystal structures, we identified the structural features for the closed, open and intermediate states. Interestingly, formation of the dimer structure was found in the open and intermediate structures. The subsequent MD simulations of the open structure in water confirmed the importance of the dimer form in stabilizing the open conformations. MD simulations of the closed and open structures in the membrane environment and the free energies for opening the F-G cassette obtained from the umbrella sampling calculations indicate that the membrane environment is important for stabilizing the F-G cassette. The dynamical network analysis indicates that Asp105 on the B-C loop plays an important role in transiting the structure from the open to intermediate. Our results thus unveil the mechanism of dimer formation and open-to-intermediate transition for CYP2B4 in the water and membrane environments.
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| 2. |
- Li, Junhao, 1989-, et al.
(författare)
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Mechanism of the Homotropic Cooperativity of Midazolam Metabolism by Cytochrome P450 3A4: Insight from Computational Studies
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Midazolam (MDZ) is a commonly used drug and is metabolized by cytochrome P450 3A4 (CYP3A4). It has been reported that the ratio of the hydroxylation products, 1'-OH-MDZ/4-OH-MDZ, is dependent on the MDZ concentration, which reflects that there exists the homotropic cooperative behavior in the CYP3A4-mediated hydroxylation of MDZ. Here, we used quantum chemistry (QC), molecular docking, conventional molecular dynamics (cMD) simulation, and Gaussian accelerated molecular dynamics (GaMD) simulation approaches to investigate the mechanism of the interactions between CYP3A4 and MDZ. Our study suggests that the H41 site, i.e. the pro-R center, is the most reactive site for the hydrogen abstraction, followed by the C1' site. However, the product 4-OH-MDZ is likely to be racemic due to the chirality inversion in the rebound step. We found that the allosteric site was not involved in the ligand cooperativity and the observation that there exists one or two MDZs in the productive site is in line with the experimental observations.
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