Lateral diffusion of bilayer lipids measured via 31P CODEX NMR

Saleem, Qasim; Lai, Angel; Morales, Hannah Hazel; Macdonald, Peter M.

doi:10.1016/j.chemphyslip.2012.08.001

Cited by 17 publications

(18 citation statements)

References 87 publications

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“…It is also not surprising to see that the highest frequency region corresponds to those cholesterol molecules experiencing singular residue contacts. We found that the bulk of these single-residue contacts were short lived, lasting for less than 2 ns, which is the characteristic time for membrane cholesterol to diffuse a distance equivalent to the contact cutoff of 6 Å in a protein-free POPC/ cholesterol bilayer and is similar to experimental determinations of the lateral diffusion of cholesterol (44,45). Thus, we consider these to be incidental contacts with the protein due to cholesterol diffusion in the membrane.…”

Section: The Microenvironment Of Cholesterol Molecules Interacting Wisupporting

confidence: 72%

Molecular Dynamics Simulations of Kir2.2 Interactions with an Ensemble of Cholesterol Molecules

Barbera

Ayee

Akpa

et al. 2018

Biophysical Journal

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Cholesterol is a major regulator of multiple types of ion channels, but the specific mechanisms and the dynamics of its interactions with the channels are not well understood. Kir2 channels were shown to be sensitive to cholesterol through direct interactions with "cholesterol-sensitive" regions on the channel protein. In this work, we used Martini coarse-grained simulations to analyze the long (μs) timescale dynamics of cholesterol with Kir2.2 channels embedded into a model membrane containing POPC phospholipid with 30 mol% cholesterol. This approach allows us to simulate the dynamic, unbiased migration of cholesterol molecules from the lipid membrane environment to the protein surface of Kir2.2 and explore the favorability of cholesterol interactions at both surface sites and recessed pockets of the channel. We found that the cholesterol environment surrounding Kir channels forms a complex milieu of different short- and long-term interactions, with multiple cholesterol molecules concurrently interacting with the channel. Furthermore, utilizing principles from network theory, we identified four discrete cholesterol-binding sites within the previously identified cholesterol-sensitive region that exist depending on the conformational state of the channel-open or closed. We also discovered that a twofold decrease in the cholesterol level of the membrane, which we found earlier to increase Kir2 activity, results in a site-specific decrease of cholesterol occupancy at these sites in both the open and closed states: cholesterol molecules at the deepest of these discrete sites shows no change in occupancy at different cholesterol levels, whereas the remaining sites showed a marked decrease in occupancy.

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Section: The Microenvironment Of Cholesterol Molecules Interacting Wisupporting

confidence: 72%

Molecular Dynamics Simulations of Kir2.2 Interactions with an Ensemble of Cholesterol Molecules

Barbera

Ayee

Akpa

et al. 2018

Biophysical Journal

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“…These values suggest that the lipid mobility is also higher in the presence of niacinamide. This quantity is indeed linked to lateral diffusion coefficients for lipids (34), and it shows the effect of the presence of the additives in the first few hundreds of nanoseconds of simulation; the long time behavior, with all systems close to a value of $0.4 A ˚2/ns, although not fully converged, is in agreement with experimental values reported for POPG lateral diffusion coefficients (38). These results are consistent with a mechanism where additives perturb the membrane on a short timescale (<1 ms), which is however sufficient for AMPs to exert their action, as demonstrated in Fig.…”

Section: Interaction Of Additive Molecules With Model Membranessupporting

confidence: 81%

Small molecules enhance the potency of natural antimicrobial peptides

Losasso

Agarwal

Waskar

et al. 2022

Biophysical Journal

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The skin-associated microbiome plays an important role in general well-being and in a variety of treatable skin conditions. In this regard, endogenous antimicrobial peptides have both a direct and indirect role in determining the composition of the microbiota. We demonstrate here that certain small molecular species can amplify the antimicrobial potency of naturally occurring antimicrobial peptides. In this study, we have used niacinamide, a form of vitamin B3 naturally found in foods and widely used in cosmetic skincare products, and two of its structural analogs, to investigate their cooperativity with the human antimicrobial peptide LL37 on the bacterium Staphylococcus aureus. We observed a clear synergistic effect of niacinamide and, to some extent, N-methylnicotinamide, whereas isonicotinamide showed no significant cooperativity with LL37. Adaptively biased molecular dynamics simulations using simplified model membrane substrates and single peptides revealed that these molecules partition into the headgroup region of an anionic bilayer used to mimic the bacterial membrane. The simulated effects on the physical properties of the simulated model membrane are well correlated with experimental activity observed in real biological assays despite the simplicity of the model. In contrast, these molecules have little effect on zwitterionic bilayers that mimic a mammalian membrane. We conclude that niacinamide and N-methylnicotinamide can therefore potentiate the activity of host peptides by modulating the physical properties of the bacterial membrane, and to a lesser extent through direct interactions with the peptide. The level of cooperativity is strongly dependent on the detailed chemistry of the additive, suggesting an opportunity to fine-tune the behavior of host peptides.

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“…These values suggest that the lipid mobility is also higher in the presence of niacinamide. This quantity is indeed linked to lateral diffusion coefficients for lipids [25] and it shows the effect of the presence of the additives in the first few hundreds of nanoseconds of simulation; the long time behaviour, with all systems close to a value of ~0.4 Å 2 /ns although not fully converged, is in agreement with experimental values reported for POPG lateral diffusion coefficients [26]. These results are consistent with a mechanism where additives perturb the membrane on a short timescale (< 1 us), which is however sufficient for AMPs to exert their action as demonstrated in Fig.…”

Section: Interaction Of Additive Molecules With Model Membranessupporting

confidence: 81%

Small molecules enhance the potency of natural antimicrobial peptides

Losasso

Agarwal

Waskar

et al. 2021

Preprint

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The skin-associated microbiome plays an important role in general well-being and in a variety of treatable conditions. In this regard, endogenous antimicrobial peptides have a role in controlling the microbial population. We demonstrate here that certain small molecular species can amplify the potency of naturally-occurring antimicrobial peptides. For example, Niacinamide is a vitamin B3 analogue naturally found in foods and widely used in topical skin care products, and here we have investigated its cooperativity with the human antimicrobial peptide LL37 on the bacterium Staphylococcus aureus. We have also studied two other structurally related B3 analogs. We observed a clear synergistic effect of niacinamide and, to some extent, methyl niacinamide, whereas isonicotinamide showed no significant cooperativity with LL37. Adaptively-biased molecular dynamics simulations revealed that the analogs partition into the head group region of an anionic bilayer used to mimic the bacterial membrane. The observed effects on the physical properties of the membrane are well correlated with experimental activity. In contrast, the analogs have little effect on zwitterionic bilayers which mimic a mammalian membrane. We conclude that these vitamin B3 analogues can potentiate the activity of host peptides by modulating the physical properties of the bacterial membrane, and to a lesser extent through direct interactions with the peptide. The level of cooperativity is strongly dependent on the detailed chemistry of the additive, suggesting an opportunity to fine-tune the behaviour of host peptides.

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Lateral diffusion of bilayer lipids measured via 31P CODEX NMR

Cited by 17 publications

References 87 publications

Molecular Dynamics Simulations of Kir2.2 Interactions with an Ensemble of Cholesterol Molecules

Molecular Dynamics Simulations of Kir2.2 Interactions with an Ensemble of Cholesterol Molecules

Small molecules enhance the potency of natural antimicrobial peptides

Small molecules enhance the potency of natural antimicrobial peptides

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