Hydration effects turn a highly stretched polymer from an entropic into an energetic spring

Polyethylene glycol (PEG) is a structurally simple and nontoxic water-soluble polymer that is widely used in medical and pharmaceutical applications as molecular linker and spacer. In such applications, PEG’s elastic response against conformational deformations is key to its function. According to text-book knowledge, a polymer reacts to the stretching of its end-to-end separation by a decrease in entropy that is due to the reduction of available conformations, which is why polymers are commonly called entropic springs. By a combination of single-molecule force spectroscopy experiments with molecular dynamics simulations in explicit water, we show that entropic hydration effects almost exactly compensate the chain conformational entropy loss at high stretching. Our simulations reveal that this entropic compensation is due to the stretching-induced release of water molecules that in the relaxed state form double hydrogen bonds with PEG. As a consequence, the stretching response of PEG is predominantly of energetic, not of entropic, origin at high forces and caused by hydration effects, while PEG backbone deformations only play a minor role. These findings demonstrate the importance of hydration for the mechanics of macromolecules and constitute a case example that sheds light on the antagonistic interplay of conformational and hydration degrees of freedom

Functionalized Fullerene for Inhibition of SARS-CoV-2 Variants

As virus outbreaks continue to pose a challenge, a nonspecific viral inhibitor can provide significant benefits, especially against respiratory viruses. Polyglycerol sulfates recently emerge as promising agents that mediate interactions between cells and viruses through electrostatics, leading to virus inhibition. Similarly, hydrophobic C60 fullerene can prevent virus infection via interactions with hydrophobic cavities of surface proteins. Here, two strategies are combined to inhibit infection of SARS-CoV-2 variants in vitro. Effective inhibitory concentrations in the millimolar range highlight the significance of bare fullerene's hydrophobic moiety and electrostatic interactions of polysulfates with surface proteins of SARS-CoV-2. Furthermore, microscale thermophoresis measurements support that fullerene linear polyglycerol sulfates interact with the SARS-CoV-2 virus via its spike protein, and highlight importance of electrostatic interactions within it. All-atom molecular dynamics simulations reveal that the fullerene binding site is situated close to the receptor binding domain, within 4 nm of polyglycerol sulfate binding sites, feasibly allowing both portions of the material to interact simultaneously

Polysulfates block SARS‐CoV‐2 uptake through electrostatic interactions

Here we report that negatively charged polysulfates can bind to the spike protein of SARS-CoV-2 via electrostatic interactions. Using a plaque reduction assay, we compare inhibition of SARS-CoV-2 by heparin, pentosan sulfate, linear polyglycerol sulfate (LPGS) and hyperbranched polyglycerol sulfate (HPGS). Highly sulfated LPGS is the optimal inhibitor, with a half-maximal inhibitory concentration (IC50) of 67 μg/mL (approx. 1.6 μM). This synthetic polysulfates exhibit more than 60-fold higher virus inhibitory activity than heparin (IC50: 4084 μg/mL), along with much lower anticoagulant activity. Furthermore, in molecular dynamics simulations, we verified that LPGS can bind stronger to the spike protein than heparin, and that LPGS can interact even more with the spike protein of the new N501Y and E484K variants. Our study demonstrates that the entry of SARS-CoV-2 into host cells can be blocked via electrostatic interaction, therefore LPGS can serve as a blueprint for the design of novel viral inhibitors of SARS-CoV-2

Association of amino acids embedded in helium droplets detected by mass spectrometry

Amino acids were embedded in helium droplets. The electron impact ionization allows for detecting positively charged glycine, valine, histidine, tryptophan and their principal fragments. Monomers and polymers with up to four amino acids are reported. Heterodimers of tryptophan and valine or histidine are observed as well as heterodimers of included fragments. The ability of these associations of molecules to form complexes with water is examined

One-pot synthesis of poly(glycerol-co-succinic acid) nanogels for dermal delivery

Polyglycerol nanogels are three-dimensional polymeric networks with a few hundred nanometer sizes and the ability to encapsulate and deliver cargos for a wide range of biomedical applications. However, time-consuming and multistep synthetic routes as well as milligram-scale production have hindered further development of these nanomaterials. In this work, we report on a straightforward synthetic method for the production of polyglycerol nanoarchitectures. Enzymatic ring-opening copolymerization of a mixture of glycidol and succinic anhydride resulted in polyglycerol nanogels with succinic acid segments in their backbone. Novozyme 435 was used as a dual catalytic agent to support ring-opening polymerization of the above-mentioned cyclic monomers as well as esterification of the produced oligomers to obtain nanogels. While succinic acid segments improved the biodegradability and loading capacity of nanogels, polyglycerol caused water solubility, high functionality, and biocompatibility. Nanogels were loaded with tacrolimus and photosensitizer 5,10,15,20-tetrakis(3-hydroxyphenyl)porphyrin (mTHPP)-a close congener of the approved photosensitizer temoporfin (mTHPC)-and their ability to improve the skin penetration of these therapeutic agents was investigated. mTHPP delivery experiments on human skin, which were quantified by fluorescence microscopy, showed that these nanogels deposit in the stratum corneum and release the loaded drug to viable epidermis of skin efficiently in comparison with commercially available base cream. Taking advantage of the straightforward synthesis as well as biodegradability, biocompatibility, high loading capacity, and efficient skin penetration, the synthesized nanogels could be used as future topical delivery systems

Characterisation of health status parameters in roe deer (Capreolus capreolus) from highly polluted areas (cadmium, lead, and PCBs) compared with areas of low pollution. II. Parasitation and histopathological findings

In this study the impact of a high contamination of the soil with the heavy metals cadmium (Cd) and lead (Pb) as well as with organochlorine compounds (PCB) on selected health status parameters in free-living roe deer was examined. In the second part the parasitic infestation and histopathological findings in the liver and kidney were investigated. As in the first part the results from roe deer from extremely highly polluted areas (regions of Bitterfeld [B] and Harz [H]) were compared with those of nearly nonpolluted areas (regions in Mecklenburg-Vorpommern [MVP] and Schleswig Holstein [SH]). In the unpolluted areas roe deer show significantly more abomasal helminths than in the polluted areas. Moreover, in the unpolluted areas a greater number of roe deer have a higher worm burden than in the polluted areas. A possible explanation for this correlation could be a higher moisture content in the soil of the SH and MVP regions, because an increased moisture content positively effects the development of external stages (e. g. eggs, larvae) of several species of abomasal helminths in roe deer (e. g. Ostertagia spp). The unpolluted areas (MVP, SH) have a proportion of 13.4% water space whereas in the polluted areas there is only 5.6%. However, within the group of one-year-old roe deer, individuals with a higher Cd contamination and a higher worm burden at the same time can be found more frequently. The incomplete immune competence in this age group could possibly explain why one-year-old roe deer react particularly sensitively. Concerning histopathological findings, lesions of the renal cortex such as tubulonephrosis, interstitial infiltration and glomerulopathy have been reported to be associated with toxic effects of cadmium. Roe deer of all three age groups showed several of these alterations, which, however, were not very pronounced. Even though, histopathological findings were observed in approximately half of the animals in each group. However, these findings were not statistically correlated to the measured cadmium levels. The two parameters gave no hint of a reduced health status of roe deer due to cadmium contamination. © 2001, Blackwell Wissenschafts-Verlag