Abstract
Here, we show that in a supramolecular system with more than 20 building blocks forming large icosahedral
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metal–organic cages (
MOCs
), using the
instant synthesis method,
it is ...possible to
kinetically trap
and control the formation of interlocking
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nanocages, giving rare
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TPB-ZnI
2
poly-
n
-catenane. The catenanes are obtained in a one-pot reaction, selectively as amorphous (
a1
) or crystalline states, as demonstrated by powder X-ray diffraction (powder XRD), thermogravimetric (TG) analysis and
1
H NMR. The 300 K
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poly-
n
-catenane single crystal X-ray diffraction (SC-XRD) structure including nitrobenzene (
1
) indicates strong guest binding with the large
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cage (i.e., internal volume
ca
. 2600 Å
3
), allowing its structural resolution. Conversely, slow self-assembly (5 days) leads to a mixture of the
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poly-
n
-catenane and a new TPB-ZnI
2
(
2
) coordination polymer (i.e., thermodynamic product), as revealed by SC-XRD. The neat grinding solid-state synthesis also yields amorphous
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poly-
n
-catenane (
a1′
), but not coordination polymers, selectively in 15 min. The dynamic behavior of the
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poly-
n
-catenanes demonstrated by the
amorphous-to-crystalline
transformation upon the uptake of
ortho
-,
meta
- and
para
-xylenes shows the potential of
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poly-
n
-catenanes as functional materials in molecular separation. Finally, combining SC-XRD of
1
and DFT calculations specific for the solid-state, the role of the guests in the stability of the 1D chains of
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nanocages is reported. Energy interactions such as interaction energies (
E
), lattice energies (
E*
), host–guest energies (
E
host-guest
) and guest-guest energies (
E
guest-guest
) were analysed considering the X-ray structure with and without the nitrobenzene guest. Not only the synthetic control achieved in the synthesis of the
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MOCs
but also their dynamic behavior either in the crystalline or amorphous phase are sufficient to raise scientific interest in areas ranging from fundamental to applied sides of chemistry and material sciences.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Cyclodextrins (CDs) are cyclic oligosaccharides able to form noncovalent water-soluble complexes useful in many different applications for the solubilization, delivery, and greater bioavailability of ...hydrophobic drugs. The complexation of 5-fluorouracil (5-FU) with natural or synthetic cyclodextrins permits the solubilization of this poorly soluble anticancer drug. In this theoretical work, the complexes between β-CD and 5-FU are investigated using molecular mechanics (MM) and molecular dynamics (MD) simulations in water. The inclusion complexes are formed thanks to the favorable intermolecular interactions between β-CD and 5-FU. Both 1:1 and 1:2 β-CD/5-FU stoichiometries are investigated, providing insight into their interaction geometries and stability over time in water. In the 1:2 β-CD/5-FU complexes, the intermolecular interactions affect the drug’s mobility, suggesting a two-step release mechanism: a fast release for the more exposed and hydrated drug molecule, with greater freedom of movement near the β-CD rims, and a slow one for the less-hydrated and well-encapsulated and confined drug. MD simulations study the intermolecular interactions between drugs and specific carriers at the atomistic level, suggesting a possible release mechanism and highlighting the role of the impact of the drug concentration on the kinetics process in water. A comparison with experimental data in the literature provides further insights.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The N1 neuraminidases (NAs) of avian and pandemic human influenza viruses contain tyrosine and asparagine, respectively, at position 347 on the rim of the catalytic site; the biological significance ...of this difference is not clear. Here, we used molecular dynamics simulation to model the effects of amino acid 347 on N1 NA interactions with sialyllacto-N-tetraoses 6'SLN-LC and 3'SLN-LC, which represent NA substrates in humans and birds, respectively. Our analysis predicted that Y347 plays an important role in the NA preference for the avian-type substrates. The Y347N substitution facilitates hydrolysis of human-type substrates by resolving steric conflicts of the Neu5Ac2-6Gal moiety with the bulky side chain of Y347, decreasing the free energy of substrate binding, and increasing the solvation of the Neu5Ac2-6Gal bond. Y347 was conserved in all N1 NA sequences of avian influenza viruses in the GISAID EpiFlu database with two exceptions. First, the Y347F substitution was present in the NA of a specific H6N1 poultry virus lineage and was associated with the substitutions G228S and/or E190V/L in the receptor-binding site (RBS) of the hemagglutinin (HA). Second, the highly pathogenic avian H5N1 viruses of the Gs/Gd lineage contained sporadic variants with the NA substitutions Y347H/D, which were frequently associated with substitutions in the HA RBS. The Y347N substitution occurred following the introductions of avian precursors into humans and pigs with N/D347 conserved during virus circulation in these hosts. Comparative evolutionary analysis of site 347 revealed episodic positive selection across the entire tree and negative selection within most host-specific groups of viruses, suggesting that substitutions at NA position 347 occurred during host switches and remained under pervasive purifying selection thereafter. Our results elucidate the role of amino acid 347 in NA recognition of sialoglycan substrates and emphasize the significance of substitutions at position 347 as a marker of host range and adaptive evolution of influenza viruses.
The interaction of heparin with antithrombin (AT) involves a specific sequence corresponding to the pentasaccharide GlcNAc/NS6S-GlcA-GlcNS3S6S-IdoA2S-GlcNS6S (AGA*IA). Recent studies have revealed ...that two AGA*IA-containing hexasaccharides, which differ in the sulfation degree of the iduronic acid unit, exhibit similar binding to AT, albeit with different affinities. However, the lack of experimental data concerning the molecular contacts between these ligands and the amino acids within the protein-binding site prevents a detailed description of the complexes. Differential epitope mapping (DEEP)-STD NMR, in combination with MD simulations, enables the experimental observation and comparison of two heparin pentasaccharides interacting with AT, revealing slightly different bound orientations and distinct affinities of both glycans for AT. We demonstrate the effectiveness of the differential solvent DEEP-STD NMR approach in determining the presence of polar residues in the recognition sites of glycosaminoglycan-binding proteins.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
We present the results of computer simulations of model polymer networks containing stiff and roughly spherical colloidal particles at 20% volume fraction. We employ the coarse-grained “dissipative ...particle dynamics” model (DPD). The filler particles may be either well dispersed or aggregated, and the strength of their interaction can be tuned by changing the parameters of the polymer−filler nonbonded potentials. By performing nonequilibrium molecular dynamics simulations, we are able to probe directly the viscoelastic behavior of the composites under oscillatory shear deformations of variable amplitude and frequency. The strength of the particle−particle interactions and sample morphology has a certain effect on the small-strain moduli. In some cases, we also observe a nonlinear viscoelastic behavior as a function of increasing shear amplitude. However, the characteristics of this nonlinearity are different from the experimentally observed “Payne effect”. Therefore, the origin of this effect does not seem to be entirely and directly related to particle−particle interactions, as is frequently assumed.
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IJS, KILJ, NUK, PNG, UL, UM
Peripherally inserted central catheters (PICCs) are central vascular access devices inserted via deep veins of the arm, also useful in critical care settings. The purpose of this article is to offer ...to a critical care clinician with good skills in central venous catheterization, but who has limited experience on PICC catheters, the basic information on how the procedure is performed and how to minimize the risks of complications or failure of the maneuver.
The main technical steps and the main precautions to be taken during PICC placement will be analyzed, with reference to the differences compared to central catheterization. Specifically, the pre-procedural phase and the intraprocedural main steps of the maneuver will be analyzed.
A dedicated Vascular Access Team is considered useful and desirable by the current literature, but when the use of the PICC proves useful or even mandatory, the intensive care physician skilled in central venous catheters can transfer skills from central to peripheral catheterization.
Differential interactions between influenza A virus protein hemagglutinin (HA) and α2→3 (avian) or α2→6 (human) sialylated glycan receptors play an important role in governing host specificity and ...adaptation of the virus. Previous analysis of HA–glycan interactions with trisaccharides showed that, in addition to the terminal sialic acid linkage, the conformation and topology of the glycans, while they are bound to HA, are key factors in regulating these interactions. Here, the solution conformation and dynamics of two representative avian and human glycan pentasaccharide receptors LSTa, Neu5Ac-α(2→3)-Gal-β(1→3)-GlcNAc-β(1→3)-Gal-β(1→4)-Glc; LSTc, (Neu5Ac-α(2→6)-Gal-β(1→4)-GlcNAc-β(1→3)-Gal-β(1→4)-Glc have been explored using nuclear magnetic resonance and molecular dynamics simulation. Analyses demonstrate that, in solution, human and avian receptors sample distinct conformations, topologies, and dynamics. These unique features of avian and human receptors in solution could represent distinct molecular characteristics for recognition by HA, thereby providing the HA–glycan interaction specificity in influenza.
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•Co-solvent MD simulation identified a putative glycosaminoglycan binding site.•Novel binding site identified at R246 and the mutated S247R bind glycosaminoglycans.•Heparan sulphate ...bridges the site between R246-S247R and PRRAR furin cleavage site.•Heparan sulphate interacts with H69, pertinent to the UK strain.
SARS-CoV-2 has rapidly spread throughout the world’s population since its initial discovery in 2019. The virus infects cells via a glycosylated spike protein located on its surface. The protein primarily binds to the angiotensin-converting enzyme-2 (ACE2) receptor, using glycosaminoglycans (GAGs) as co-receptors. Here, we performed bioinformatics and molecular dynamics simulations of the spike protein to investigate the existence of additional GAG binding sites on the receptor-binding domain (RBD), separate from previously reported heparin-binding sites. A putative GAG binding site in the N-terminal domain (NTD) of the protein was identified, encompassing residues 245–246. We hypothesized that GAGs of a sufficient length might bridge the gap between this site and the PRRARS furin cleavage site, including the mutation S247R. Docking studies using GlycoTorch Vina and subsequent MD simulations of the spike trimer in the presence of dodecasaccharides of the GAGs heparin and heparan sulfate supported this possibility. The heparan sulfate chain bridged the gap, binding the furin cleavage site and S247R. In contrast, the heparin chain bound the furin cleavage site and surrounding glycosylation structures, but not S247R. These findings identify a site in the spike protein that favors heparan sulfate binding that may be particularly pertinent for a better understanding of the recent UK and South African strains. This will also assist in future targeted therapy programs that could include repurposing clinical heparan sulfate mimetics.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Avian influenza A viruses, which can also propagate between humans, present serious pandemic threats, particularly in Asia. The specificity (selectivity) of interactions between the recognition ...protein hemagglutinin (HA) of the virus capsid and the glycoconjugates of host cells also contributes to the efficient spread of the virus by aerosol between humans. Some avian origin viruses, such as H1N1 (South Carolina 1918), have improved their selectivity for human receptors by mutation in the HA receptor binding site, to generate pandemic viruses. Molecular details and dynamics of glycan–HA interactions are of interest, both in predicting the pandemic potential of a new emerging strain and in searching for new antiviral drugs. Two complementary techniques, 1H saturation transfer difference (1H STD) nuclear magnetic resonance and molecular dynamics (MD) simulation, were applied to analyze the interaction of the new H7 (A/Anhui/1/13 H7N9) with LSTa Neu5Ac α(2→3) Gal β(1→3) GlcNAc β(1→3) Gal β(1→4) Glc and LSTc Neu5Ac α(2→6) Gal β(1→4) GlcNAc β(1→3) Gal β(1→4) Glc pentasaccharides, models of avian and human receptor glycans. Their interactions with H7 were analyzed for the first time using 1H STD and MD, revealing structural and dynamic behavior that could not be obtained from crystal structures, and contributing to glycan–HA specificity. This highlighted aspects that could affect glycan–HA recognition, including the mutation H7 G228S, which increases H2 and H3 specificity for the human receptor. Finally, interactions between LSTc and H7 were compared with those between LSTc and H1 of H1N1 (South Carolina 1918), contributing to our understanding of the recognition ability of HAs.
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IJS, KILJ, NUK, PNG, UL, UM
Unplanned extubation (UE) in Intensive Care Units (ICU) is an indicator of quality and safety of care. UEs are classified in: accidental extubations, if involuntarily caused during nursing care or ...medical procedures; self-extubation, if determined by the patient him/herself. In scientific literature, the cumulative incidence of UEs varies from 0.3% to 35.8%. The aim of this study is to explore the incidence of UEs in an Italian university general ICU adopting a well-established protocol of tracheal tube nursing management and fixation.
retrospective observational study. We enrolled all patients undergone to invasive mechanical ventilation from 1st January 2008 to 31st December 2016.
in the studied period 3422 patients underwent to endotracheal intubation. The UEs were 35: 33 self extubations (94%) and 2 accidental extubations (6%). The incidence of UEs calculated on 1497 patients intubated for more than 24 hours was 2.34%. Instead, it was 1.02%, if we consider the whole number of intubated patients. Only in 9 (26%) cases out of 35 UEs the patient was re-intubated. No deaths consequent to UE were recorded.
The incidence of UEs in this study showed rates according to the minimal values reported in scientific literature. A standardized program of endotracheal tube management (based on an effective and comfortable fixing system) seems to be a safe and a valid foundation in order to maintain the UE episodes at minimum rates.
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