Identification of lamellar and hexagonal phases in negatively stained phospholipid-water systems

Tinker, David O.; Pinteric, L.

doi:10.1021/bi00781a020

Cited by 27 publications

(9 citation statements)

References 17 publications

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“…18,19 These structures are inverted in the sense that the polar headgroups are oriented toward interior aqueous cores with diameters as small as 3 nm. 20 The actual equilibrium radius of an inverted micelle could be larger as dictated by the intrinsic or spontaneous radius of curvature of the constituent lipids. 21 In turn, assuming a bilayer thickness of 4 nm this would suggest that LNP systems composed of pure cationic lipid should exhibit limit sizes with diameters in the range of 11 nm or larger, which is essentially a bilayer surrounding an aqueous interior with diameter as small as 3 nm.…”

Section: Resultsmentioning

confidence: 99%

Lipid Nanoparticles Containing siRNA Synthesized by Microfluidic Mixing Exhibit an Electron-Dense Nanostructured Core

et al. 2012

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Lipid nanoparticles (LNP) containing ionizable cationic lipids are the leading systems for enabling therapeutic applications of siRNA; however, the structure of these systems has not been defined. Here we examine the structure of LNP siRNA systems containing DLinKC2-DMA(an ionizable cationic lipid), phospholipid, cholesterol and a polyethylene glycol (PEG) lipid formed using a rapid microfluidic mixing process. Techniques employed include cryo-transmission electron microscopy, 31P NMR, membrane fusion assays, density measurements, and molecular modeling. The experimental results indicate that these LNP siRNA systems have an interior lipid core containing siRNA duplexes complexed to cationic lipid and that the interior core also contains phospholipid and cholesterol. Consistent with experimental observations, molecular modeling calculations indicate that the interior of LNP siRNA systems exhibits a periodic structure of aqueous compartments, where some compartments contain siRNA. It is concluded that LNP siRNA systems formulated by rapid mixing of an ethanol solution of lipid with an aqueous medium containing siRNA exhibit a nanostructured core. The results give insight into the mechanism whereby LNP siRNA systems are formed, providing an understanding of the high encapsulation efficiencies that can be achieved and information on methods of constructing more sophisticated LNP systems.

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Section: Resultsmentioning

confidence: 99%

Lipid Nanoparticles Containing siRNA Synthesized by Microfluidic Mixing Exhibit an Electron-Dense Nanostructured Core

et al. 2012

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“…Figure 3 shows how K11 affects also membranes mainly constituted by CL (CL 50% / POPC 50%). It should be noted that in the cases of CL and POPE, the addition of POPC was necessary for the formation of a MLV, due to their intrinsic shape and different T m [32,[62][63][64][65][66][67][68].…”

Section: K11 Selectivity Perturbs the Core Of Liposomes With Bacteriamentioning

confidence: 99%

Antimicrobial Peptide K11 Selectively Recognizes Bacterial Biomimetic Membranes and Acts by Twisting Their Bilayers

et al. 2020

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K11 is a synthetic peptide originating from the introduction of a lysine residue in position 11 within the sequence of a rationally designed antibacterial scaffold. Despite its remarkable antibacterial properties towards many ESKAPE bacteria and its optimal therapeutic index (320), a detailed description of its mechanism of action is missing. As most antimicrobial peptides act by destabilizing the membranes of the target organisms, we investigated the interaction of K11 with biomimetic membranes of various phospholipid compositions by liquid and solid-state NMR. Our data show that K11 can selectively destabilize bacterial biomimetic membranes and torque the surface of their bilayers. The same is observed for membranes containing other negatively charged phospholipids which might suggest additional biological activities. Molecular dynamic simulations reveal that K11 can penetrate the membrane in four steps: after binding to phosphate groups by means of the lysine residue at the N-terminus (anchoring), three couples of lysine residues act subsequently to exert a torque in the membrane (twisting) which allows the insertion of aromatic side chains at both termini (insertion) eventually leading to the flip of the amphipathic helix inside the bilayer core (helix flip and internalization).

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“…The thickness of the bilayer (=2Q) is -4 nm (41). The diameter of HI, rods in natural PE systems is 6-8 nm (3,(48)(49)(50). Using this diameter (7.0 nm) as the diameter of the inverted micelle (equals 2 rm) yields a diameter for the monolayer-enveloped structure of 11.0 nm.…”

Section: C I + -Ncmentioning

confidence: 99%

Inverted micellar structures in bilayer membranes. Formation rates and half-lives

Siegel¹

1984

Biophysical Journal

169

103

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Two sorts of inverted micellar structures have previously been proposed to explain morphological and 31P-NMR observations of bilayer systems. These structures only form in systems with components that can adopt the inverse hexagonal (HII) phase. LIP (lipidic particles) are intrabilayer structures, whereas IMI (inverted micellar intermediates) are structures that form between apposed bilayers. Here, we calculate the formation rates and half-lives of these structures to determine which (or if either) of these proposed structures is a likely explanation of the data. Calculations for the egg phosphatidylethanolamine and the Ca+-cardiolipin systems show that IMI form orders of magnitude faster than LIP, which should form slowly, if at all. This result is probably true in general, and indicates that "lipidic particle" electron micrograph images probably represent interbilayer structures, as some have previously proposed. It is shown here that IMI are likely intermediates in the lamellar----HII phase transitions and in the process of membrane fusion in some systems. The calculated formation rates, half-lives, and vesicle-vesicle fusion rates are in agreement with this observation.

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Identification of lamellar and hexagonal phases in negatively stained phospholipid-water systems

Cited by 27 publications

References 17 publications

Lipid Nanoparticles Containing siRNA Synthesized by Microfluidic Mixing Exhibit an Electron-Dense Nanostructured Core

Lipid Nanoparticles Containing siRNA Synthesized by Microfluidic Mixing Exhibit an Electron-Dense Nanostructured Core

Antimicrobial Peptide K11 Selectively Recognizes Bacterial Biomimetic Membranes and Acts by Twisting Their Bilayers

Inverted micellar structures in bilayer membranes. Formation rates and half-lives

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