scholarly journals CHARMM-GUI Membrane Builder for Lipid Nanoparticles with Ionizable Cationic Lipids and PEGylated Lipids

2021 ◽  
Author(s):  
Soohyung Park ◽  
Yeol Kyo Choi ◽  
Seonghoon Kim ◽  
Jumin Lee ◽  
Wonpil Im
Keyword(s):  
Molecular Level ◽  
State Of The Art ◽  
Fluid Phase ◽  
Lipid Nanoparticles ◽  
Cationic Lipids ◽  
Head Group ◽  
Head Groups ◽  
Pegylated Lipids ◽  
High Concentrations ◽  
Art Delivery

A lipid nanoparticle (LNP) formulation is a state-of-the-art delivery system for genetic drugs such as DNA, mRNA, and siRNA, which is successfully applied to COVID-19 vaccines and gains tremendous interest in therapeutic applications. Despite its importance, a molecular-level understanding of the LNP structures and dynamics is still lacking, which makes a rational LNP design almost impossible. In this work, we present an extension of CHARMM-GUI Membrane Builder to model and simulate all-atom LNPs with various (ionizable) cationic lipids and PEGylated lipids (PEG-lipids). These new lipid types can be mixed with any existing lipid types with or without a biomolecule of interest, and the generated systems can be simulated using various molecular dynamics engines. As a first illustration, we considered model LNP membranes with DLin-KC2-DMA (KC2) or DLin-MC3-DMA (MC3) without PEG-lipids. The results from these model membranes are consistent with those from the two previous studies albeit with mild accumulation of neutral MC3 in the bilayer center. To demonstrate Membrane Builder's capability of building a realistic LNP patch, we generated KC2- or MC3-containing LNP membranes with high concentrations of cholesterol and ionizable cationic lipids together with 2 mol% PEG-lipids. We observe that PEG-chains are flexible, which can be more preferentially extended laterally in the presence of cationic lipids due to the attractive interactions between their head groups and PEG oxygen. The presence of PEG-lipids also relaxes the lateral packing in LNP membranes, and the area compressibility modulus (KA) of LNP membranes with cationic lipids fit into typical KA of fluid-phase membranes. Interestingly, the interactions between PEG oxygen and head group of ionizable cationic lipids induce a negative curvature. We hope that this LNP capability in Membrane Builder can be useful to better characterize various LNPs with or without genetic drugs for a rational LNP design.

scholarly journals Niosomes based on synthetic cationic lipids for gene delivery: the influence of polar head-groups on the transfection efficiency in HEK-293, ARPE-19 and MSC-D1 cells

2015 ◽  
Vol 13 (4) ◽  
pp. 1068-1081 ◽  
Author(s):  
E. Ojeda ◽  
G. Puras ◽  
M. Agirre ◽  
J. Zárate ◽  
S. Grijalvo ◽  
...  
Keyword(s):  
Gene Delivery ◽  
Transfection Efficiency ◽  
Cationic Lipids ◽  
Head Group ◽  
Polar Head Group ◽  
Hek 293 ◽  
Polar Head ◽  
Head Groups

We designed niosomes based on three lipids that differed only in the polar-head group to analyze their influence on the transfection efficiency.

scholarly journals Transgene expression in mice of the Opa1 mitochondrial transmembrane protein through bicontinuous cubic lipoplexes containing gemini imidazolium surfactants

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Mónica Muñoz-Úbeda ◽  
Martina Semenzato ◽  
Anais Franco-Romero ◽  
Elena Junquera ◽  
Emilio Aicart ◽  
...  
Keyword(s):  
Transgene Expression ◽  
Transmembrane Protein ◽  
Quantitative Polymerase Chain Reaction ◽  
Genetic Material ◽  
Cationic Lipids ◽  
Head Group ◽  
Polar Head ◽  
Cubic Phases ◽  
Head Groups ◽  
Bicontinuous Cubic

Abstract Background Lipoplexes are non-viral vectors based on cationic lipids used to deliver DNA into cells, also known as lipofection. The positively charge of the hydrophilic head-group provides the cationic lipids the ability to condensate the negatively charged DNA into structured complexes. The polar head can carry a large variety of chemical groups including amines as well as guanidino or imidazole groups. In particular, gemini cationic lipids consist of two positive polar heads linked by a spacer with different length. As for the hydrophobic aliphatic chains, they can be unsaturated or saturated and are connected to the polar head-groups. Many other chemical components can be included in the formulation of lipoplexes to improve their transfection efficiency, which often relies on their structural features. Varying these components can drastically change the arrangement of DNA molecules within the lamellar, hexagonal or cubic phases that are provided by the lipid matrix. Lipofection is widely used to deliver genetic material in cell culture experiments but the simpler formulations exhibit major drawbacks related to low transfection, low specificity, low circulation half-life and toxicity when scaled up to in vivo experiments. Results So far, we have explored in cell cultures the transfection ability of lipoplexes based on gemini cationic lipids that consist of two C16 alkyl chains and two imidazolium polar head-groups linked with a polyoxyethylene spacer, (C16Im)2(C4O). Here, PEGylated lipids have been introduced to the lipoplex formulation and the transgene expression of the Opa1 mitochondrial transmembrane protein in mice was assessed. The addition of PEG on the surface of the lipid mixed resulted in the formation of Ia3d bicontinuous cubic phases as determined by small angle X-ray scattering. After a single intramuscular administration, the cubic lipoplexes were accumulated in tissues with tight endothelial barriers such as brain, heart, and lungs for at least 48 h. The transgene expression of Opa1 in those organs was identified by western blotting or RNA expression analysis through quantitative polymerase chain reaction. Conclusions The expression reported here is sufficient in magnitude, duration and toxicity to consolidate the bicontinuous cubic structures formed by (C16Im)2(C4O)-based lipoplexes as valuable therapeutic agents in the field of gene delivery. Graphical Abstract

Toward living nanomachines

2018 ◽  
Author(s):  
Christof Mast ◽  
Friederike Möller ◽  
Moritz Kreysing ◽  
Severin Schink ◽  
Benedikt Obermayer ◽  
...  
Keyword(s):  
Molecular Evolution ◽  
Thermal Gradient ◽  
Molecular Level ◽  
Minimal System ◽  
Thermal Gradients ◽  
Temperature Oscillations ◽  
Fluid Convection ◽  
Inanimate Matter ◽  
High Concentrations ◽  
Periodic Temperature

How does inanimate matter become transformed into animate matter? Living systems evolve by replication and selection at the molecular level and this chapter considers how to establish a synthetic, minimal system that can support molecular evolution and thus life. Molecular evolution cannot be explained by starting with high concentrations of activated chemicals that react toward their chemical equilibrium; persistent non-equilibria are required to maintain continuous reactivity and we especially consider thermal gradients as an early driving force for Darwinian molecular evolution. The temperature difference across water-filled compartments implements a laminar fluid convection with periodic temperature oscillations that allow for the melting and replication of DNA. Simultaneously, dissolved molecules are moved along the thermal gradient by an effect called thermophoresis. The combined result is an efficient molecule trap that exponentially favors long over short DNA and thus maintains complexity. Future experiments will reveal how thermal gradients could actively drive the Darwinian process of replication and selection.

scholarly journals Exchange Speed of Four-Component Nanorotors Correlates with Hammett Substituent Constants

Chemistry ◽  
2021 ◽  
Vol 3 (1) ◽  
pp. 116-125
Author(s):  
Yi-Fan Li ◽  
Amit Ghosh ◽  
Pronay Kumar Biswas ◽  
Suchismita Saha ◽  
Michael Schmittel
Keyword(s):  
Linear Correlation ◽  
Bond Cleavage ◽  
Head Group ◽  
Ligand Interaction ◽  
Exchange Frequency ◽  
Rate Determining Step ◽  
Head Groups ◽  
Substituent Constants ◽  
First Time ◽  
Determining Factor

Three distinct four-component supramolecular nanorotors were prepared, using, for the first time, bipyridine instead of phenanthroline stations in the stator. Following our established self-sorting protocol to multicomponent nanodevices, the nanorotors were self-assembled by mixing the stator, rotators with various pyridine head groups, copper(I) ions and 1,4-diazabicyclo[2.2.2]octane (DABCO). Whereas the exchange of a phenanthroline vs. a bipyridine station did not entail significant changes in the rotational exchange frequency, the para-substituents at the pyridine head group of the rotator had drastic consequences on the speed: 4-OMe (k298 = 35 kHz), 4-H (k298 = 77 kHz) and 4-NO2 (k298 = 843 kHz). The exchange frequency (log k) showed an excellent linear correlation with both the Hammett substituent constants and log K of the copper(I)–ligand interaction, proving that rotator–copper(I) bond cleavage is the key determining factor in the rate-determining step.

Electron Transport from QA to Thymoquinone in a Synechococcus Oxygen-Evolving Photosystem II Preparation: Role of QB and Binding Affinity of Thymoquinone to the QB Site

1993 ◽  
Vol 48 (3-4) ◽  
pp. 174-178 ◽  
Author(s):  
Kazuhiko Satoh ◽  
Yasuhiro Kashino ◽  
Hiroyuki Koike
Keyword(s):  
Binding Affinity ◽  
Turnover Rate ◽  
Side Chain ◽  
Head Group ◽  
Binding Affinities ◽  
Ps Ii ◽  
Thermophilic Cyanobacteria ◽  
High Concentrations ◽  
Oxygen Evolving

Abstract We have recently shown that binding affinities of benzoquinones can be estimated by two methods in photosystem (PS) II particles (K. Satoh et al., Biochim. Biophys. Acta 1102, 45-52 (1992)). Using these methods we calculated the binding affinity of thymoquinone (2-methyl-5-isopropyl-p-benzoquinone) to the QB site and studied how the quinone accepts electrons in oxygen-evolving PS II particles isolated from the thermophilic cyanobacteria, Synechococcus elongatus and S. vulcanus. The results are as follows: (1) The binding constant of thymoqui­ none to the QB site determined by several methods was around 0.33 mᴍ . (2) At low thymoquinone concentrations the quinone was supposed to accept electrons via QB-plastoquinone, whereas at high concentrations the quinone seemed to bind to the QB site and accept an electron directly from Q-A. Lower rates of photoreduction of the quinone at high concentrations were attributed to a slower turnover rate of the quinone at the QB site than that of endogenous plastoquinone. (3) A model for the function of plastoquinone at the QB site, which can explain all the results, was presented. According to this model, the plastoquinone molecule at the QB site is not replaced by another plastoquinone molecule. Instead, it transfers electrons to pool plastoquinone molecules by turning over its head group but remaining its long side chain bound to the PS II complexes.

Albumin absorption by canine bronchial epithelium

1989 ◽  
Vol 66 (6) ◽  
pp. 2772-2777 ◽  
Author(s):  
L. G. Johnson ◽  
P. W. Cheng ◽  
R. C. Boucher
Keyword(s):  
Gel Filtration ◽  
Fluid Phase ◽  
Bronchial Epithelium ◽  
Bathing Solution ◽  
Michaelis Constant ◽  
Airway Epithelia ◽  
Ussing Chambers ◽  
Bronchial Epithelia ◽  
Surface Liquid ◽  
High Concentrations

Albumin concentrations in airway surface liquid are low compared with plasma. To investigate the mechanisms that generate albumin gradients across airway epithelia, we have investigated whether active albumin absorption is a feature of bronchial epithelia. Freshly excised canine bronchi were mounted in Ussing chambers and short-circuited. Permeability coefficients of 14C-labeled canine albumin (Palb) were measured in the mucosal-to-submucosal (M----S) and submucosal-to-mucosal (S----M) directions in conductance-matched tissues. Mean steady-state values for Palb in the absorptive (M----S) direction (5.97 +/- 1.89 x 10(-7) cm/s) were significantly greater than rates in the S----M direction (1.09 +/- 0.41 x 10(-7) cm/s). Simultaneous measurements detected no asymmetry of transport of the fluid phase marker [3H]inulin. Gel filtration chromatography demonstrated that the majority of the radiolabel released into the submucosal bathing solution represented albumin fragments. Albumin fragments per se were not transported because no asymmetries in permeabilities of albumin fragments isolated from spontaneous degradation of tracer were detected. Decreasing the temperature of the bathing solution from 37 to 4 degrees C completely inhibited net albumin absorption. [14C]albumin transport was saturated by addition of high concentrations of unlabeled albumin (estimated Michaelis constant = 1.6 x 10(-3) M). These results demonstrate that albumin is absorbed by a low-affinity process that may contribute to the maintenance of low albumin concentrations in secretions.

Dramatic influence of the hydroxy functionality of azasugar moiety in the head group region of tocopherol-based cationic lipids on in vitro gene transfection efficacies

2021 ◽  
Author(s):  
Venkanna Muripiti ◽  
Brijesh Lohchania ◽  
Venkatesh Ravula ◽  
Shireesha Manturthi ◽  
Srujan Marepally ◽  
...  
Keyword(s):  
Gene Transfection ◽  
Cationic Lipids ◽  
Head Group ◽  
Nonviral Vectors

Cationic lipids have been effectively used as nonviral vectors for the delivery of polynucleic acids into the cytosol.

scholarly journals Bio-Catalysis and Biomedical Perspectives of Magnetic Nanoparticles as Versatile Carriers

2019 ◽  
Vol 5 (3) ◽  
pp. 42 ◽  
Author(s):  
Muhammad Bilal ◽  
Shahid Mehmood ◽  
Tahir Rasheed ◽  
Hafiz M. N. Iqbal
Keyword(s):  
Magnetic Field ◽  
Magnetic Properties ◽  
Magnetic Nanoparticles ◽  
Molecular Level ◽  
State Of The Art ◽  
Volume Ratio ◽  
Controlled Drug Delivery ◽  
High Mass ◽  
Biological Interactions ◽  
Magnetic Carriers

In recent years, magnetic nanoparticles (MNPs) have gained increasing attention as versatile carriers because of their unique magnetic properties, biocatalytic functionalities, and capabilities to work at the cellular and molecular level of biological interactions. Moreover, owing to their exceptional functional properties, such as large surface area, large surface-to-volume ratio, and mobility and high mass transference, MNPs have been employed in several applications in different sectors such as supporting matrices for enzymes immobilization and controlled release of drugs in biomedicine. Unlike non-magnetic carriers, MNPs can be easily separated and recovered using an external magnetic field. In addition to their biocompatible microenvironment, the application of MNPs represents a remarkable green chemistry approach. Herein, we focused on state-of-the-art two majorly studied perspectives of MNPs as versatile carriers for (1) matrices for enzymes immobilization, and (2) matrices for controlled drug delivery. Specifically, from the applied perspectives of magnetic nanoparticles, a series of different applications with suitable examples are discussed in detail. The second half is focused on different metal-based magnetic nanoparticles and their exploitation for biomedical purposes.

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