Understanding the role of lipids in signaling through atomistic and multiscale simulations of cell membranes

Peer reviewe

Is Lipid Specificity Key to the Potential Antiviral Activity of Mouthwash Reagent Chlorhexidine against SARS-CoV-2?

Chlorhexidine (CHX), a popular antibacterial drug, is widely used for oral health. Emerging pieces of evidence suggest that commercially available chlorhexidine mouthwash formulations are effective in suppressing the spread of SARS-CoV-2, possibly through destabilization of the viral lipid envelope. CHX is known for its membrane-active properties; however, the molecular mechanism revealing how it damages the viral lipid envelope is yet to be understood. Here we used extensive conventional and umbrella sampling simulations to quantify the effects of CHX on model membranes mimicking the composition of the SARS-CoV-2 outer lipid membrane as well as the host plasma membrane. Our results show that the lipid composition and physical properties of the membrane play an important role in binding and insertion, with CHX binding favorably to the viral membrane over the plasma membrane. Among the simulated lipids, CHX preferentially binds to anionic lipids, PS and PI, which are more concentrated in the viral membrane. The deeper and stable binding of CHX to the viral membrane results in more pronounced swelling of the membrane laterally with a thinning of the bilayer. The overall free energies of pore formation are strongly reduced for the viral membrane compared to the plasma membrane; however, CHX has a larger concentration-dependent effect on free energies of pore formation in the plasma membrane than the viral membrane. The results indicate that CHX is less toxic to the human plasma membrane at low concentrations. Our simulations reveal that CHX facilitates pore formation by the combination of thinning the membrane and accumulation at the water defect. This study provides insights into the mechanism underlying the anti-SARS-CoV-2 potency of CHX, supporting its potential for application as an effective and safe oral rinse agent for preventing viral transmission

Long-chain GM1 gangliosides alter transmembrane domain registration through interdigitation

Extracellular and cytosolic leaflets in cellular membranes are distinctly different in lipid composition, yet they contribute together to signaling across the membranes. Here we consider a mechanism based on long-chain gangliosides for coupling the extracellular and cytosolic membrane leaflets together. Based on atomistic molecular dynamics simulations, we find that long-chain GM1 in the extracellular leaflet exhibits a strong tendency to protrude into the opposing bilayer leaflet. This interdigitation modulates the order in the cytosolic monolayer and thereby strengthens the interaction and coupling across a membrane. Coarse-grained simulations probing longer time scales in large membrane systems indicate that GM1 in the extracellular leaflet modulates the phase behavior in the cytosolic monolayer. While short-chain GM1 maintains phase-symmetric bilayers with a strong membrane registration effect, the situation is altered with long-chain GM1. Here, the significant interdigitation induced by long-chain GM1 modulates the behavior in the cytosolic GM1-free leaflet, weakening and slowing down the membrane registration process. The observed physical interaction mechanism provides a possible means to mediate or foster transmembrane communication associated with signal transduction. (C) 2017 Elsevier B.V. All rights reserved.Peer reviewe

Experimental determination and computational interpretation of biophysical properties of lipid bilayers enriched by cholesteryl hemisuccinate

AbstractCholesteryl hemisuccinate (CHS) is one of the cholesterol-mimicking detergents not observed in nature. It is, however, widely used in protein crystallography, in biochemical studies of proteins, and in pharmacology. Here, we performed an extensive experimental and theoretical study on the behavior of CHS in lipid membranes rich in unsaturated phospholipids. We found that the deprotonated form of CHS (that is the predominant form under physiological conditions) does not mimic cholesterol very well. The protonated form of CHS does better in this regard, but also its ability to mimic the physical effects of cholesterol on lipid membranes is limited. Overall, although ordering and condensing effects characteristic to cholesterol are present in systems containing any form of CHS, their strength is appreciably weaker compared to cholesterol. Based on the considerable amount of experimental and atomistic simulation data, we conclude that these differences originate from the fact that the ester group of CHS does not anchor it in an optimal position at the water–membrane interface. The implications of these findings for considerations of protein–cholesterol interactions are briefly discussed

A cholesterol analog stabilizes the human β2-adrenergic receptor nonlinearly with temperature

In cell membranes, G protein-coupled receptors (GPCRs) interact with cholesterol, which modulates their assembly, stability, and conformation. Previous studies have shown how cholesterol modulates the structural properties of GPCRs at ambient temperature. Here, we characterized the mechanical, kinetic, and energetic properties of the human beta(2)-adrenergic receptor (beta(2)AR) in the presence and absence of the cholesterol analog cholesteryl hemisuccinate (CHS) at room temperature (25 degrees C), at physiological temperature (37 degrees C), and at high temperature (42 degrees C). We found that CHS stabilized various structural regions of beta(2)AR differentially, which changed nonlinearly with temperature. Thereby, the strongest effects were observed for structural regions that are important for receptor signaling. Moreover, at 37 degrees C, but not at 25 degrees or 42 degrees C, CHS caused beta(2)AR to increase and stabilize conformational substates to adopt to basal activity. These findings indicate that the nonlinear, temperature-dependent action of CHS in modulating the structural and functional properties of this GPCR is optimized for 37 degrees C.Peer reviewe

Underpinning beneficial maize response to application of minimally processed homogenates of red and brown seaweeds

Sap from the fresh seaweed Kappaphycus alvarezii (KA) has been reported to improve crop growth, quality, and stress alleviation. However, limited studies are reported for the minimally processed aqueous homogenates (MPHs) derived from dry seaweeds. The present investigation was envisaged to characterize the MPHs from the red seaweed KA and a brown seaweed Sargassum wightii (SW) and also assess the effect of foliar application on maize (Zea mays) crop performance when applied alone or in proportions ranging from 0% to 100%. Two doses (0.35% and 0.7%) were compared with control. Both the MPHs contained several compounds like retronecine, tyrosyl-glycine, hexyl 2-furoate, 1-phosphatidyl-1D-myo-inositol, 12-(2,3-dihydroxycyclopentyl)-2-dodecanone, and trihomomethionine and many others that have known bioactivity for enhancing plant growth and providing stress tolerance. Both doses of MPHs enhanced crop growth and yield; however, the best response was in general observed at a lower dose. The MPH of SW at 100% gave the highest seed yield at a lower dose, which was also on par with that obtained under a lower dose of 100% KA. Other combinations, 80:20 and 40:60 KA : SW, were also found to give comparable yields. The highest dose of 100% MPH of SW was found on par with control, a phenomenon that was investigated in detail with respect to metabolites and antioxidant profile in leaves as well as membrane modeling. Higher ROS and certain sugar and organic acids were observed in 100% MPH of SW at a higher dose, although none of the antioxidant enzymes were significantly affected, nor was there any change in membrane characteristics of the leaf with respect to control as well as lower dose. Improvements in the seed yield were attributed to improved photosynthate production on account of higher dry matter accumulation in the MPH-treated plants, which may also be attributed to the presence of bioactive compounds in the biostimulants. In the future, it is imperative to direct scientific investigations towards the quantification and identification of the most effective concentrations of these compounds within MPHs to optimize plant responses. The study indicated the beneficial use of the MPHs towards increasing crop production by employing optimum dose as foliar spray to crops

Enzymatic Oxidation of Cholesterol : Properties and Functional Effects of Cholestenone in Cell Membranes

Peer reviewe

A cholesterol analog stabilizes the human β2-adrenergic receptor nonlinearly with temperature

In cell membranes, G protein-coupled receptors (GPCRs) interact with cholesterol, which modulates their assembly, stability, and conformation. Previous studies have shown how cholesterol modulates the structural properties of GPCRs at ambient temperature. Here, we characterized the mechanical, kinetic, and energetic properties of the human β2-adrenergic receptor (β2AR) in the presence and absence of the cholesterol analog cholesteryl hemisuccinate (CHS) at room temperature (25°C), at physiological temperature (37°C), and at high temperature (42°C). We found that CHS stabilized various structural regions of β2AR differentially, which changed nonlinearly with temperature. Thereby, the strongest effects were observed for structural regions that are important for receptor signaling. Moreover, at 37°C, but not at 25° or 42°C, CHS caused β2AR to increase and stabilize conformational substates to adopt to basal activity. These findings indicate that the nonlinear, temperature-dependent action of CHS in modulating the structural and functional properties of this GPCR is optimized for 37°C.acceptedVersionPeer reviewe

Factors accounting for dimer stability.

<p>(a) The snapshot showed the presence of intra-molecular Lys²⁸-Asp²³ slat-bridge in monomer-1 of Dimer1. Here the corresponding Lys²⁸ and Asp²³ were colored according to atom type: C in red, O in yellow, N in blue and H in white. (b) The time dependence of minimum distance between amide N of Lys²⁸ and carboxyl O of Asp²³ in monomer-1 of Dimer1, as highlighted in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0071308#pone-0071308-g007" target="_blank">Figure 7a</a>. (c) 3D-plot showing the inter-peptide hydrogen-bonding interactions within Dimer1 (last 200 ns average). The notation used here for leveling H-bond between a pair of residues was XA-YB, where X was the amino acid residue of peptide-1 with its corresponding residue number A and Y was the residue of peptide-2 with its corresponding residue number B.</p

Binding, Conformational Transition and Dimerization of Amyloid-β Peptide on GM1-Containing Ternary Membrane: Insights from Molecular Dynamics Simulation

<div><p>Interactions of amyloid-β (Aβ) with neuronal membrane are associated with the progression of Alzheimer’s disease (AD). Ganglioside GM1 has been shown to promote the structural conversion of Aβ and increase the rate of peptide aggregation; but the exact nature of interaction driving theses processes remains to be explored. In this work, we have carried out atomistic-scale computer simulations (totaling 2.65 µs) to investigate the behavior of Aβ monomer and dimers in GM1-containing raft-like membrane. The oligosaccharide head-group of GM1 was observed to act as scaffold for Aβ-binding through sugar-specific interactions. Starting from the initial helical peptide conformation, a β-hairpin motif was formed at the C-terminus of the GM1-bound Aβ-monomer; that didn’t appear in absence of GM1 (both in fluid POPC and liquid-ordered cholesterol/POPC bilayers and also in aqueous medium) within the simulation time span. For Aβ-dimers, the β-structure was further enhanced by peptide-peptide interactions, which might influence the propensity of Aβ to aggregate into higher-ordered structures. The salt-bridges and inter-peptide hydrogen bonds were found to account for dimer stability. We observed spontaneous formation of intra-peptide D²³-K²⁸ salt-bridge and a turn at V²⁴GSN²⁷ region - long been accepted as characteristic structural-motifs for amyloid self-assembly. Altogether, our results provide atomistic details of Aβ-GM1 and Aβ-Aβ interactions and demonstrate their importance in the early-stages of GM1-mediated Aβ-oligomerisation on membrane surface.</p></div