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PLoS Computational Biology Jul 2023The phase separation model for transcription suggests that transcription factors (TFs), coactivators, and RNA polymerases form biomolecular condensates around active...
The phase separation model for transcription suggests that transcription factors (TFs), coactivators, and RNA polymerases form biomolecular condensates around active gene loci and regulate transcription. However, the structural details of condensates remain elusive. In this study, for Nanog, a master TF in mammalian embryonic stem cells known to form protein condensates in vitro, we examined protein structures in the condensates using residue-level coarse-grained molecular simulations. Human Nanog formed micelle-like clusters in the condensate. In the micelle-like cluster, the C-terminal disordered domains, including the tryptophan repeat (WR) regions, interacted with each other near the cluster center primarily via hydrophobic interaction. In contrast, hydrophilic disordered N-terminal and DNA-binding domains were exposed on the surface of the clusters. Electrostatic attractions of these surface residues were responsible for bridging multiple micelle-like structures in the condensate. The micelle-like structure and condensate were dynamic and liquid-like. Mutation of tryptophan residues in the WR region which was implicated to be important for a Nanog function resulted in dissolution of the Nanog condensate. Finally, to examine the impact of Nanog cluster to DNA, we added DNA fragments to the Nanog condensate. Nanog DNA-binding domains exposed to the surface of the micelle-like cluster could recruit more than one DNA fragments, making DNA-DNA distance shorter.
Topics: Animals; Humans; DNA; Embryonic Stem Cells; Micelles; Transcription Factors; Tryptophan
PubMed: 37486948
DOI: 10.1371/journal.pcbi.1011321 -
Proceedings of the National Academy of... Nov 2022DNA recombination is a ubiquitous process that ensures genetic diversity. Contrary to textbook pictures, DNA recombination, as well as generic DNA translocations, occurs...
DNA recombination is a ubiquitous process that ensures genetic diversity. Contrary to textbook pictures, DNA recombination, as well as generic DNA translocations, occurs in a confined and highly entangled environment. Inspired by this observation, here, we investigate a solution of semiflexible polymer rings undergoing generic cutting and reconnection operations under spherical confinement. Our setup may be realized using engineered DNA in the presence of recombinase proteins or by considering micelle-like components able to form living (or reversibly breakable) polymer rings. We find that in such systems, there is a topological gelation transition, which can be triggered by increasing either the stiffness or the concentration of the rings. Flexible or dilute polymers break into an ensemble of short, unlinked, and segregated rings, whereas sufficiently stiff or dense polymers self-assemble into a network of long, linked, and mixed loops, many of which are knotted. We predict that the two phases should behave qualitatively differently in elution experiments monitoring the escape dynamics from a permeabilized container. Besides shedding some light on the biophysics and topology of genomes undergoing DNA reconnection in vivo, our findings could be leveraged in vitro to design polymeric complex fluids-e.g., DNA-based complex fluids or living polymer networks-with desired topologies.
Topics: Polymers; Micelles; DNA; Biophysics; Recombinases
PubMed: 36279471
DOI: 10.1073/pnas.2207728119 -
Proceedings of the Japan Academy.... 2023Micelles are useful and widely applied molecular assemblies, formed from amphiphilic molecules, in water. The majority of amphiphiles possess an alkyl chain as the... (Review)
Review
Micelles are useful and widely applied molecular assemblies, formed from amphiphilic molecules, in water. The majority of amphiphiles possess an alkyl chain as the hydrophobic part. Amphiphiles bearing hydrophilic and hydrophobic polymer chains generate so-called polymeric micelles in water. This review focuses on the recent progress of "aromatic micelles", formed from bent polyaromatic/aromatic amphiphiles, for the development of third-generation micelles. Thanks to multiple host-guest interactions, e.g., the hydrophobic effect and π-π/CH-π interactions, the present micelles display wide-ranging uptake abilities toward various hydrophobic compounds in water. In addition to such host functions, new stimuli-responsive aromatic micelles with pH, light, and redox switches, aromatic oligomer micelles, saccharide-coated aromatic micelles, and related cycloalkane-based micelles were recently developed by our group.
Topics: Micelles; Polymers; Water; Hydrophobic and Hydrophilic Interactions
PubMed: 36631075
DOI: 10.2183/pjab.99.002 -
The Journal of Membrane Biology Oct 2022Molecular dynamics simulations are an attractive tool for understanding lipid/peptide self-assembly but can be plagued by inaccuracies when the system sizes are too...
Molecular dynamics simulations are an attractive tool for understanding lipid/peptide self-assembly but can be plagued by inaccuracies when the system sizes are too small. The general guidance from self-assembly simulations of homogeneous micelles is that the total number of surfactants should be three to five times greater than the equilibrium aggregate number of surfactants per micelle. Herein, the heuristic is tested on the more complicated self-assembly of lipids and amphipathic peptides using the Cooke and Martini 3 coarse-grained models. Cooke model simulations with 50 to 1000 lipids and no peptide are dominated by finite-size effects, with usually one aggregate (micelle or nanodisc) containing most of the lipids forming at each system size. Approximately 200 systems of different peptide/lipid (P/L) ratios and sizes of up to 1000 lipids yield a "finite-size phase diagram" for peptide driven self-assembly, including a coexistence region of micelles and discs. Insights from the Cooke model are applied to the assembly of dimyristoylphosphatidylcholine and the ELK-neutral peptide using the Martini 3 model. Systems of 150, 450, and 900 lipids with P/L = 1/6.25 form mixtures of lipid-rich discs that agree in size with experiment and peptide-rich micelles. Only the 150-lipid system shows finite-size effects, which arise from the long-tailed distribution of aggregate sizes. The general rule of three to five times the equilibrium aggregate size remains a practical heuristic for the Cooke and Martini 3 systems investigated here.
Topics: Micelles; Dimyristoylphosphatidylcholine; Molecular Dynamics Simulation; Peptides; Surface-Active Agents
PubMed: 35854128
DOI: 10.1007/s00232-022-00255-9 -
Journal of Pharmaceutical Sciences Mar 2023Multi-injection pharmaceutical products such as insulin must be formulated to prevent aggregation and microbial contamination. Small-molecule preservatives and nonionic...
Multi-injection pharmaceutical products such as insulin must be formulated to prevent aggregation and microbial contamination. Small-molecule preservatives and nonionic surfactants such as poloxamer 188 (P188) are thus often employed in protein drug formulations. However, mixtures of preservatives and surfactants can induce aggregation and even phase separation over time, despite the fact that all components are well dissolvable when used alone in aqueous solution. A systematic study is conducted here to understand the phase behavior and morphological causes of aggregation of P188 in the presence of the preservatives phenol and benzyl alcohol, primarily using small-angle x-ray scattering (SAXS). Based on SAXS results, P188 remains as unimers in solution when below a certain phenol concentration. Upon increasing the phenol concentration, a regime of micelle formation is observed due to the interaction between P188 and phenol. Further increasing the phenol concentration causes mixtures to become turbid and phase-separate over time. The effect of benzyl alcohol on the phase behavior is also investigated.
Topics: Poloxamer; Micelles; Scattering, Small Angle; X-Rays; X-Ray Diffraction; Surface-Active Agents; Water; Preservatives, Pharmaceutical; Phenols; Benzyl Alcohols; Solutions
PubMed: 36150467
DOI: 10.1016/j.xphs.2022.09.019 -
Analytical Chemistry Jun 2018Creating new functional building blocks that expand the versatility of nanostructures depends on bottom-up self-assembly of amphiphilic biomolecules. Inspired by the...
Creating new functional building blocks that expand the versatility of nanostructures depends on bottom-up self-assembly of amphiphilic biomolecules. Inspired by the unique physicochemical properties of hydrophobic perfluorocarbons, coupled with the powerful functions of nucleic acids, we herein report the synthesis of a series of diperfluorodecyl-DNA conjugates (PF-DNA) which can efficiently self-assemble into micelles in aqueous solution. On the basis of the micelle structure, both target binding affinity and enzymatic resistance of the DNA probe can be enhanced. In addition, based on the hydrophobic effect, the PF-DNA micelles (PFDM) can actively anchor onto the cell membrane, offering a promising tool for cell-surface engineering. Finally, the PFDM can enter cells, which is significant for designing carriers for intracellular delivery. The combined advantages of the DNA micelle structure and the unique physicochemical properties of perfluorocarbons make these PFDM promising for applications in bioimaging and biomedicine.
Topics: DNA; Fluorocarbons; Halogenation; Micelles; Molecular Structure
PubMed: 29770690
DOI: 10.1021/acs.analchem.8b01005 -
ACS Biomaterials Science & Engineering Jul 2022Block copolymer micelles have demonstrated great promise in the solubilization of hydrophobic drugs, but an understanding of the blood stability of the drug-laden...
Block copolymer micelles have demonstrated great promise in the solubilization of hydrophobic drugs, but an understanding of the blood stability of the drug-laden micelles is needed for therapeutic advancement of micelle technologies. Following intravenous administration, mPEG-CL and mPEG-LA micelles have demonstrated quick release of their cargo and disassembly in blood, but the prevailing mechanisms of micelle disruption and key biomacromolecules driving this disruption have yet to be elucidated. Although protein interactions with solid polymeric nanoparticles have been characterized, not much is known regarding protein interactions with dynamic block copolymer micelles. Herein, we characterize the interaction of bovine and human serum albumins (BSA and HSA) with polymeric micelles, mPEG-CL and mPEG-LA, using protein fluorescence, isothermal titration calorimetry (ITC), and circular dichroism (CD) spectroscopy. We find that BSA and HSA have interactions with mPEG-CL, while only HSA is observed to weakly interact with mPEG-LA. Protein fluorescence suggests that binding of HSA to mPEG-CL and mPEG-LA is driven by electrostatic interactions. ITC suggests an interaction between serum albumin and mPEG-CL block copolymers driven by hydrogen bonding and electrostatic interactions in physiological MOPS-buffered saline, while mPEG-LA has no measurable interaction with either of the serum albumins. CD spectroscopy demonstrates that the protein secondary structure is intact in both proteins in the presence of mPEG-CL and mPEG-LA. Overall, BSA is not always predictive of polymeric interactions with HSA. Understanding of interactions between serum proteins and block copolymer micelles and the exact mechanisms of destabilization will direct the rational design of block copolymer systems for improving blood stability.
Topics: Animals; Cattle; Humans; Hydrophobic and Hydrophilic Interactions; Micelles; Nanoparticles; Polymers; Serum Albumin
PubMed: 35767337
DOI: 10.1021/acsbiomaterials.2c00016 -
Nature Nanotechnology Feb 2021Real-world bioelectronics applications, including drug delivery systems, biosensing and electrical modulation of tissues and organs, largely require biointerfaces at the...
Real-world bioelectronics applications, including drug delivery systems, biosensing and electrical modulation of tissues and organs, largely require biointerfaces at the macroscopic level. However, traditional macroscale bioelectronic electrodes usually exhibit invasive or power-inefficient architectures, inability to form uniform and subcellular interfaces, or faradaic reactions at electrode surfaces. Here, we develop a micelle-enabled self-assembly approach for a binder-free and carbon-based monolithic device, aimed at large-scale bioelectronic interfaces. The device incorporates a multi-scale porous material architecture, an interdigitated microelectrode layout and a supercapacitor-like performance. In cell training processes, we use the device to modulate the contraction rate of primary cardiomyocytes at the subcellular level to target frequency in vitro. We also achieve capacitive control of the electrophysiology in isolated hearts, retinal tissues and sciatic nerves, as well as bioelectronic cardiac sensing. Our results support the exploration of device platforms already used in energy research to identify new opportunities in bioelectronics.
Topics: Biocompatible Materials; Biosensing Techniques; Carbon; Electrodes; Equipment Design; Membranes, Artificial; Micelles; Nanostructures; Porosity
PubMed: 33288948
DOI: 10.1038/s41565-020-00805-z -
Journal of Animal Science Dec 2021The aim of the present study was to explore the influences of varying doses of micelle silymarin (0%, 0.05%, 0.1%, and 0.2%) supplementation on sows' feed intake, milk...
Micelle silymarin supplementation to sows' diet from day 109 of gestation to entire lactation period enhances reproductive performance and affects serum hormones and metabolites.
The aim of the present study was to explore the influences of varying doses of micelle silymarin (0%, 0.05%, 0.1%, and 0.2%) supplementation on sows' feed intake, milk yields, serum hormones, and litter growth using 40 multiparous sows (Landrace × Yorkshire, parity from 3 to 5) from the 109th prenatal day to the 21st postnatal day. Each treatment included 10 sows and each sow was used as an experimental unit. On weaning day, litter weight and litter weight gain were linearly improved (P < 0.01, both), corresponding to the increasing dose of silymarin micelle in the diet. Also, litter weight, litter weight gain, and average daily gain (ADG) of piglets born to treated sows exceeded (P < 0.05) those of offspring from the control sows (0% micelle silymarin). Feed intake in week 1, week 2, and the entire lactation period was increased (linear, P < 0.01) as micelle silymarin dose increased. Body weight (BW) loss of sows during lactation was linearly reduced (P = 0.003) with the increasing amounts of micelle silymarin. Average daily milk yields during lactation were also linearly increased (P = 0.002) in treated sows, exceeding (P = 0.046) that of control sows. Also, uniform increases were observed (P = 0.037) in fat content in milk produced by treated sows on day 14 of lactation. Epinephrine concentrations and aspartate aminotransferase (AST) activity in sow serum on day 21 postpartum were linearly declined (P = 0.010) as micelle silymarin dose increased, and were both declined (P < 0.05) in treated sows compared with the control. In addition, treated sows' serum had higher activity of superoxide dismutase (SOD) at parturition and glutathione peroxidase (GSH-Px), lower oxidized glutathione (GSSG) concentrations, and GSSG/GSH (glutathione) ratio (all, P < 0.01) on day 21 of lactation. Moreover, offspring from micelle silymarin-treated sows tended to (0.05 < P <0.1) have higher serum catalase (CAT) activity and total antioxidant capacity (T-AOC) concentrations. Taken together, the results showed that sows fed increasing levels of micelle silymarin from the 109th prenatal day to the 21st postnatal day had an incremental dose-dependent effect on higher feed intake, diminished BW loss, greater milk yields, and greater litter weight at weaning, and 0.2% of micelle silymarin could be optimal to achieve the better effect.
Topics: Animals; Diet; Dietary Supplements; Female; Hormones; Lactation; Micelles; Pregnancy; Silymarin; Swine
PubMed: 34850001
DOI: 10.1093/jas/skab354 -
Journal of Controlled Release :... Jan 2023New and improved nanomaterials are constantly being developed for biomedical purposes. Nanomaterials based on elastin-like polypeptides (ELPs) have increasingly shown... (Review)
Review
New and improved nanomaterials are constantly being developed for biomedical purposes. Nanomaterials based on elastin-like polypeptides (ELPs) have increasingly shown potential over the past two decades. These polymers are artificial proteins of which the design is based on human tropoelastin. Due to this similarity, ELP-based nanomaterials are biodegradable and therefore well suited to drug delivery. The assembly of ELP molecules into nanoparticles spontaneously occurs at temperatures above a transition temperature (T). The ELP sequence influences both the T and the physicochemical properties of the assembled nanomaterial. Nanoparticles with desired properties can hence be designed by choosing the appropriate sequence. A promising class of ELP nanoparticles are micelles assembled from amphiphilic ELP diblock copolymers. Such micelles are generally uniform and well defined. Furthermore, site-specific attachment of cargo to the hydrophobic block results in micelles with the cargo shielded inside their core, while conjugation to the hydrophilic block causes the cargo to reside in the corona where it is available for interactions. Such control over particle design is one of the main contributing factors for the potential of ELP-based micelles as a drug delivery system. Additionally, the micelles are easily loaded with protein or peptide-based cargo by expressing it as a fusion protein. Small molecule drugs and other cargo types can be either covalently conjugated to ELP domains or physically entrapped inside the micelle core. This review aims to give an overview of ELP-based micelles and their applications in nanomedicine.
Topics: Humans; Micelles; Elastin; Nanomedicine; Peptides; Drug Delivery Systems
PubMed: 36526018
DOI: 10.1016/j.jconrel.2022.12.033