The role of plasmalogens, Forssman lipids, and sphingolipid hydroxylation in modulating the biophysical properties of the epithelial plasma membrane

Wilson, Katie A.; Fairweather, Stephen J.; MacDermott-Opeskin, Hugo; Wang, Lily; Morris, Richard A.; O’Mara, Megan L.

doi:10.1063/5.0040887

Cited by 14 publications

(20 citation statements)

References 106 publications

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“…Molecular simulation of bacterial membranes, and biological membranes in general, has advanced significantly over the past 20 years, with larger, more complex and more realistic simulations becoming feasible (Marrink et al 2019 ; Wilson et al 2020b ; Im and Khalid 2020 ). Advances in forcefields, particularly the CHARMM atomistic forcefield and MARTINI coarse-grained forcefield (Marrink et al 2004 , 2007 ; Wu et al 2014 ; Lee et al 2019a ), coupled with increasing hardware capabilities and improvements in simulation tooling, has enabled simulations of membranes approaching realistic chemical diversity in constituent protein and lipid components (Ingólfsson et al 2014 , 2017 ; Reddy et al 2015 ; Wilson et al 2020a , 2021 ).…”

Section: Understanding the Role Of Lipid-mediated Resistance For Anti...mentioning

confidence: 99%

Lipid-mediated antimicrobial resistance: a phantom menace or a new hope?

2022

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The proposition of a post-antimicrobial era is all the more realistic with the continued rise of antimicrobial resistance. The development of new antimicrobials is failing to counter the ever-increasing rates of bacterial antimicrobial resistance. This necessitates novel antimicrobials and drug targets. The bacterial cell membrane is an essential and highly conserved cellular component in bacteria and acts as the primary barrier for entry of antimicrobials into the cell. Although previously under-exploited as an antimicrobial target, the bacterial cell membrane is attractive for the development of novel antimicrobials due to its importance in pathogen viability. Bacterial cell membranes are diverse assemblies of macromolecules built around a central lipid bilayer core. This lipid bilayer governs the overall membrane biophysical properties and function of its membrane-embedded proteins. This mini-review will outline the mechanisms by which the bacterial membrane causes and controls resistance, with a focus on alterations in the membrane lipid composition, chemical modification of constituent lipids, and the efflux of antimicrobials by membrane-embedded efflux systems. Thorough insight into the interplay between membrane-active antimicrobials and lipid-mediated resistance is needed to enable the rational development of new antimicrobials. In particular, the union of computational approaches and experimental techniques for the development of innovative and efficacious membrane-active antimicrobials is explored.

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Section: Understanding the Role Of Lipid-mediated Resistance For Anti...mentioning

confidence: 99%

Lipid-mediated antimicrobial resistance: a phantom menace or a new hope?

2022

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“…Of course, the question remains to which extend the here-resolved hydrophobic pattern can prevail in nature, where evolution is subject to many additional constraints. Purely composition-wise, verification with a coarse-grained native epithelial membrane model (36) suggests that the here-resolved functionality persists in more realistic membrane environments (see Fig. S7).…”

Section: Discussionmentioning

confidence: 88%

“…A cholesterol attractor (D 3 K 3 L 8 K 3 D 3 ) was inserted into a native epithelial membrane model ((36), “Membrane 1”) and a 2 μ s NPT MD simulation is performed with a 20 fs timestep, of which the first 500 ns were used for equilibration purposes. Temperature was coupled to 310 K using velocity rescaling ( τ = 1 ps, with separate coupling groups for the membrane, peptide, and solvent).…”

Section: Supplementary Informationmentioning

confidence: 99%

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Physics-based inverse design of cholesterol attracting transmembrane helices reveals a paradoxical role of hydrophobic length

Methorst

2021

Preprint

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The occurrence of linear cholesterol-recognition motifs in alpha-helical transmembrane domains has long been debated. Here, we demonstrate the ability of a genetic algorithm guided by coarse-grained molecular dynamics simulations---a method coined evolutionary molecular dynamics (evo-MD)---to directly resolve the sequence which maximally attracts/sorts cholesterol within a single-pass alpha-helical transmembrane domain (TMDs). We illustrate that the evolutionary landscape of cholesterol attraction in membrane proteins is characterized by a sharp, well-defined global optimum. Surprisingly, this optimal solution features an unusual short hydrophobic block, consisting of typically only eight short chain hydrophobic amino acids, surrounded by three successive lysines. Owing to the membrane thickening effect of cholesterol, cholesterol-enriched ordered phases favor TMDs characterized by a long rather than a short hydrophobic length. However, this short hydrophobic pattern evidently offers a pronounced net advantage for the binding of free cholesterol in both coarse-grained and atomistic simulations. Attraction is mediated by the unique ability of cholesterol to snorkel within the hydrophobic core of the membrane and thereby shield deeply located lysines from the unfavorable hydrophobic surrounding. Since this mechanism of attraction is of a thermodynamic nature and is not based on molecular shape specificity, a large diversity of sub-optimal cholesterol attracting sequences can exist. The puzzling sequence variability of proposed linear cholesterol-recognition motifs is thus consistent with sub-optimal, unspecific binding of cholesterol. Importantly, since evo-MD uniquely enables the targeted design of recognition motifs for distinct fluid lipid membranes, we foresee wide applications for evo-MD in the biological and biomedical fields.

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“…Previous studies have shown that alterations in lipid distribution, acyl tail diversity, and lipid hydroxylation all contribute to the rate of cholesterol flip-flop. 15,16,37 Conversely, the oxidized cholesterol species flip-flop faster when the site of oxidation is on the tail group (3.89 ± 0.03 × 10 6 s −1 ) compared to when the ring is oxidized (1.43 ± 0.01 × 10 6 s −1 ). The change in rate of flip-flop between the ring-oxidized and tail-oxidized cholesterols can be explained by the difference in charge distribution across the molecule.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Site of Cholesterol Oxidation Impacts Its Localization and Domain Formation in the Neuronal Plasma Membrane

Wilson

Wang

O’Mara

2021

ACS Chem. Neurosci.

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Cholesterol is integral to the structure of mammalian cell membranes. Oxidation of cholesterol alters how it behaves in the membrane and influences the membrane biophysical properties. Elevated levels of oxidized cholesterol are associated with neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and Huntington’s disease. Previous work has investigated the impact of oxidized cholesterol in the context of simple model membrane systems. However, there is a growing body of literature that shows that complex membranes possessing physiological phospholipid distributions have different properties from those of binary or trinary model membranes. In the current work, the impact of oxidized cholesterol on the biophysical properties of a complex neuronal plasma membrane is investigated using coarse-grained Martini molecular dynamics simulations. Comparison of the native neuronal membrane to neuronal membranes containing 10% tail-oxidized or 10% head-oxidized cholesterol shows that the site of oxidization changes the behavior of the oxidized cholesterol in the membrane. Furthermore, species-specific domain formation is observed between each oxidized cholesterol and minor lipid classes. Although both tail-oxidized and head-oxidized cholesterols modulate the biophysical properties of the membrane, smaller changes are observed in the complex neuronal membrane than seen in the previous work on simple binary or trinary model membranes. This work highlights the presence of compensatory effects of lipid diversity in the complex neuronal membrane. Overall, this study improves our molecular-level understanding of the effects of oxidized cholesterol on the properties of neuronal tissue and emphasizes the importance of studying membranes with realistic lipid compositions.

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The role of plasmalogens, Forssman lipids, and sphingolipid hydroxylation in modulating the biophysical properties of the epithelial plasma membrane

Cited by 14 publications

References 106 publications

Lipid-mediated antimicrobial resistance: a phantom menace or a new hope?

Lipid-mediated antimicrobial resistance: a phantom menace or a new hope?

Physics-based inverse design of cholesterol attracting transmembrane helices reveals a paradoxical role of hydrophobic length

Site of Cholesterol Oxidation Impacts Its Localization and Domain Formation in the Neuronal Plasma Membrane

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