A comparative study of polyethylene oxide (PEO) using different coarse-graining methods.

Polyethylene oxide (PEO) holds significant importance in the field of batteries due to its high processability, intrinsic properties, and potential for high ionic conductivity. Achieving simulation at different scales is crucial for gaining a comprehensive understanding of its properties and thus improving them. In this context, we conducted a comparative study on the molecular physical structure, thermodynamic, and dynamic properties of PEO using three distinct coarse-grained (CG) procedures and all-atom (AA) simulations. The three CG simulation procedures involved modeling with MARTINI forcefield, SPICA forcefield, and an IBI derived potential from AA simulations. The AA simulation has been performed using the class 2 pcff+ forcefield. The ensuing simulated densities align significantly with the literature data, indicating the reliability of our approach. The solubility parameter from the AA simulation closely corresponds to literature reported values. MARTINI and SPICA yield almost similar solubility parameters, consistent with the similar density predicted by both the forcefields. Notably, SPICA forcefield closely reproduces the intermolecular structure of atomistic systems, as evidenced by radial distribution function (RDF). It also comprehensively replicates the distribution of radius of gyration (Rg) and the end-to-end distance (Re) of the atomistic samples. IBI ranks second to SPICA in emulating the structural properties of the atomistic systems, such as Rg, Re, and RDF. However, IBI falls short in accurately representing the solubility parameter of the amorphous PEO samples, while MARTINI does not provide an accurate representation of the structural properties of the systems. The use of SPICA forcefield results in enhanced dynamics of the systems in comparison with IBI and MARTINI.

Macrophages show higher levels of engulfment after disruption of cis interactions between CD47 and the checkpoint receptor SIRPα.

The macrophage checkpoint receptor SIRPα signals against phagocytosis by binding CD47 expressed on all cells - including macrophages. Here, we found that inhibiting cis interactions between SIRPα and CD47 on the same macrophage increased engulfment ('eating') by approximately the same level as inhibiting trans interactions. Antibody blockade of CD47, as pursued in clinical trials against cancer, was applied separately to human-derived macrophages and to red blood cell (RBC) targets for phagocytosis, and both scenarios produced surprisingly similar increases in RBC engulfment. Blockade of both macrophages and targets resulted in hyper-phagocytosis, and knockdown of macrophage-CD47 likewise increased engulfment of 'foreign' cells and particles, decreased the baseline inhibitory signaling of SIRPα, and linearly increased binding of soluble CD47 in trans, consistent with cis-trans competition. Many cell types express both SIRPα and CD47, including mouse melanoma B16 cells, and CRISPR-mediated deletions modulate B16 phagocytosis, consistent with cis-trans competition. Additionally, soluble SIRPα binding to human CD47 displayed on Chinese hamster ovary (CHO) cells was suppressed by SIRPα co-display, and atomistic computations confirm SIRPα bends and binds CD47 in cis Safety and efficacy profiles for CD47-SIRPα blockade might therefore reflect a disruption of both cis and trans interactions.

Minimal "Self" peptides that inhibit phagocytic clearance and enhance delivery of nanoparticles.

Foreign particles and cells are cleared from the body by phagocytes that must also recognize and avoid clearance of "self" cells. The membrane protein CD47 is reportedly a "marker of self" in mice that impedes phagocytosis of self by signaling through the phagocyte receptor CD172a. Minimal "Self" peptides were computationally designed from human CD47 and then synthesized and attached to virus-size particles for intravenous injection into mice that express a CD172a variant compatible with hCD47. Self peptides delay macrophage-mediated clearance of nanoparticles, which promotes persistent circulation that enhances dye and drug delivery to tumors. Self-peptide affinity for CD172a is near the optimum measured for human CD172a variants, and Self peptide also potently inhibits nanoparticle uptake mediated by the contractile cytoskeleton. The reductionist approach reveals the importance of human Self peptides and their utility in enhancing drug delivery and imaging.

Dynamic domains in polymersomes: mixtures of polyanionic and neutral diblocks respond more rapidly to changes in calcium than to pH.

Chemical triggering of membrane domain dynamics is of broad relevance to cell signaling through lipid bilayers and might also be exploited in application of phase-separated vesicles. Here we describe the morphodynamics and remixing kinetics of spotted polymersomes made with mixtures of polyanionic and neutral amphiphiles plus calcium. Addition of the calcium chelator EDTA to vesicle dispersions produced a decrease in domain size within minutes, whereas increasing the pH with NaOH led to the viscous fingering of domains and decreased domain size over hours. Although the latter suggests that the charge of the polyanion contributes to domain formation, the remixing of more negative chains at high pH is surprising. Domain roughening at high pH is also accelerated by EDTA, which highlights the dominance of cross-bridging. Importantly, even though vesicles were perturbed only externally, the inner and outer leaflets remain coupled throughout, consistent with molecular dynamics simulations and suggestive of an order-disorder transition that underlies the remixing kinetics.

Morphologies of charged diblock copolymers simulated with a neutral coarse-grained model.

We present the results of coarse grained molecular dynamics simulation using a charge free model that is able to capture different regions of the morphological phase diagram of charged diblock copolymers. Specifically, we were able to reproduce many phases of the poly(acrylic acid)-(1,4)-polybutadiene (PAA-PBA) diblock copolymer, Ca(2+) and water systems as a function of pH and calcium concentration with short-range LJ type potentials. The morphologies observed range from bilayers to cylinders to spherical micelles. Such polyanionic/cationic amphiphiles in water typically present multiple challenges for molecular simulations, particularly due to the many charge interactions that are long ranged and computationally costly. Further, it is precisely these interactions that are thought to modulate large amphiphile assemblies of interest such as lipid rafts. However, our model is able to reproduce different morphologies due to pH and with or without the addition of Ca(2+) as well as the lateral phase segregation and the domain registration observed in neutral and charged diblock copolymer mixtures. The results suggest that the overall effect of charges is a local structural rearrangement that renormalizes the steric repulsion between the headgroups. This simple model, which is devoid of charges, is able to reproduce the complex phase diagram and can be used to investigate collective phenomena in these charged systems such as domain formation and registration or colocalization of lipid rafts across bilayer leaflets.

Characterization of membrane-protein interactions for the leucine transporter from Aquifex aeolicus by molecular dynamics calculations.

Multinanosecond molecular dynamics (MD) simulations have been employed to characterize the interaction of an integral membrane protein (IMP), the leucine transmitter from Aquifex aeolicus (Yamashita et al., Nature 2005, 437, 215-223), with hydrated lipid bilayer membranes in their physiologically relevant liquid crystalline phases. Analysis of the MD trajectories for dimyristoyl phosphatidylcholine (DMPC), 1-palmitoyl-2-oleoyl phosphatidylcholine (POPC), and 1-palmitoyl-2-oleoyl phosphatidylethanolamine (POPE) focused on the contacts between aromatic and basic side chains of the IMP with the lipid head groups and water. Structural fluctuations of the IMP were investigated as well as the contact dynamics of neighboring lipids. In characterizing the IMP-membrane systems, the behaviors of the protein's cytoplasmic and periplasmic parts are considered separately. All three lipid membranes show a rather similar overall level of association with the IMP. However, for DMPC there is a better matching of the membrane core to the hydrophobic transmembrane portion of the IMP. The closed cytoplasmic end of the IMP exhibits a higher degree of association with lipids than the more open periplasmic end, an observation which correlates with the more compact structure and a slower dynamics of surrounding lipids.

Solvation of coumarin 314 at water/air interfaces containing anionic surfactants. I. Low coverage.

Through the use of molecular dynamics techniques, we analyze equilibrium and dynamical aspects of the solvation of Coumarin 314 adsorbed at water/air interfaces in the presence of sodium dodecyl sulfate surfactant molecules. Three different coverages in the submonolayer regime were considered, 500, 250, and 100 A(2)/SDS molecule. The surfactant promotes two well-differentiated solvation environments, which can be clearly distinguished in terms of their structures for the largest surfactant coverage considered. The first one is characterized by the probe lying adjacent or exterior to two-dimensional spatial domains formed by clustered surfactant molecules. A second type of solvation environment is found in which the coumarin appears embedded within compact surfactant domains. Equilibrium and dynamical aspects of the interfacial orientation of the probe are investigated. Our results show a gradual transition from parallel to perpendicular dipolar alignment of the probe with respect to the interface as the concentration of surfactant rho(s) increases. The presence of the surfactant leads to an increase in the roughness and in the characteristic width of the water/air interface. These modifications are also manifested by the decorrelation times for the probe reorientational dynamics, which become progressively slower with rho(s) in both solvation states, although much more pronounced for the embedded ones. The dynamical characteristics of the solvation responses of the charged interfaces are also analyzed, and the implications of our findings to the interpretation of available experimental measurements are discussed.