From Molecular Dynamics to Supramolecular Organization: The Role of PIM Lipids in the Originality of the<i>Mycobacterial</i>Plasma Membrane

Brown, Chelsea M.; Corey, Robin A.; Gao, Ya; Choi, Yeol Kyo; Gilleron, Martine; Destainville, Nicolas; Fullam, Elizabeth; Im, Wonpil; Stansfeld, Phillip J.; Chavent, Matthieu

doi:10.1101/2022.06.29.498153

Cited by 4 publications

(2 citation statements)

References 85 publications

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“…AcPIM2, along with the related four-tailed lipid diacyl phosphatidylinositol dimannoside (Ac2PIM2), is unique to mycobacteria and highly abundant in the inner membrane (59)(60)(61). AcPIM2 comprises ~10% of the M. smegmatis inner membrane (62), with Ac2PIM2 proposed to comprise almost all of the inner leaflet of the inner membrane. In the structure, the phosphatidylinositol headgroup of AcPIM2 is positioned to form contacts with Pro166, Lys 173, and Met561 of NuoL, and Gln450 of NuoM (Fig.…”

Section: The Mycobacterial Phospholipid Acpim2 Binds the Nuom-nuol In...mentioning

confidence: 99%

Structure of mycobacterial respiratory Complex I

Liang

Plourde

Bueler

et al. 2022

Preprint

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Oxidative phosphorylation, the combined activity of the electron transport chain (ETC) and adenosine triphosphate synthase, has emerged as a valuable target for the treatment of infection by Mycobacterium tuberculosis and other mycobacteria. The mycobacterial ETC is highly branched with multiple dehydrogenases transferring electrons to a membrane-bound pool of menaquinone and multiple oxidases transferring electrons from the pool. The proton-pumping type I nicotinamide adenine dinucleotide (NADH) dehydrogenase (Complex I) is found at low abundance in the plasma membranes of mycobacteria in typical in vitro culture conditions and is often considered dispensable. We found that growth of Mycobacterium smegmatis in carbon-limited conditions greatly increased the abundance of Complex I and allowed isolation of a rotenone-sensitive preparation of the enzyme. Determination of the structure of the complex by cryoEM revealed the "orphan" two-component response regulator protein MSMEG_2064 as a subunit of the assembly. MSMEG_2064 in the complex occupies a site similar to the proposed redox sensing subunit NDUFA9 in eukaryotic Complex I. An apparent purine nucleoside triphosphate within the NuoG subunit resembles the GTP-derived molybdenum cofactor in homologous formate dehydrogenase enzymes. The membrane region of the complex binds acyl phosphatidylinositol dimannoside, a characteristic three-tailed lipid from the mycobacterial membrane. The structure also shows menaquinone, which is preferentially used over ubiquinone by gram-positive bacteria, in two different positions along the quinone channel and suggests that menaquinone interacts more extensively than ubiquinone with a key catalytic histidine residue in the enzyme.

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Section: The Mycobacterial Phospholipid Acpim2 Binds the Nuom-nuol In...mentioning

confidence: 99%

Structure of mycobacterial respiratory Complex I

Liang

Plourde

Bueler

et al. 2022

Preprint

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“…There is also a clear difference in the permeation data of charged molecules through other membranes. For the charged molecules, OMs have energy barriers of 40-60 kcal/mol, while the energy barriers for lipid membranes can be relatively low [44,45]. This may be a distinguishing feature of mycolic acid membranes compared to membranes composed of lipids only.…”

Section: Regression Model Of Diffusion Activation Barriers Based On S...mentioning

confidence: 99%

Free Energy Barriers for Passive Drug Transport through the Mycobacterium tuberculosis Outer Membrane: A Molecular Dynamics Study

Steshin,

Vasyankin,

Shirokova

et al. 2024

IJMS

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The emergence of multi-drug-resistant tuberculosis strains poses a significant challenge to modern medicine. The development of new antituberculosis drugs is hindered by the low permeability of many active compounds through the extremely strong bacterial cell wall of mycobacteria. In order to estimate the ability of potential antimycobacterial agents to diffuse through the outer mycolate membrane, the free energy profiles, the corresponding activation barriers, and possible permeability modes of passive transport for a series of known antibiotics, modern antituberculosis drugs, and prospective active drug-like molecules were determined using molecular dynamics simulations with the all-atom force field and potential of mean-force calculations. The membranes of different chemical and conformational compositions, density, thickness, and ionization states were examined. The typical activation barriers for the low-mass molecules penetrating through the most realistic membrane model were 6–13 kcal/mol for isoniazid, pyrazinamide, and etambutol, and 19 and 25 kcal/mol for bedaquilin and rifampicin. The barriers for the ionized molecules are usually in the range of 37–63 kcal/mol. The linear regression models were derived from the obtained data, allowing one to estimate the permeability barriers from simple physicochemical parameters of the diffusing molecules, notably lipophilicity and molecular polarizability.

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Molecular Dynamics and Other HPC Simulations for Drug Discovery

Kotev,

Diaz Gonzalez

2023

Methods in Molecular Biology

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From Molecular Dynamics to Supramolecular Organization: The Role of PIM Lipids in the Originality of theMycobacterialPlasma Membrane

Cited by 4 publications

References 85 publications

Structure of mycobacterial respiratory Complex I

Structure of mycobacterial respiratory Complex I

Free Energy Barriers for Passive Drug Transport through the Mycobacterium tuberculosis Outer Membrane: A Molecular Dynamics Study

Molecular Dynamics and Other HPC Simulations for Drug Discovery

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