Engineered nanoparticles as Selinexor drug delivery systems across the cell membrane and related signaling pathways in cancer cells.

In the present work, molecular dynamics simulation is applied to evaluate the drug carrier efficiency of graphene oxide nanoflake (GONF) for loading of Selinexor (SXR) drug as well as the drug delivery by 2D material through the membrane in aqueous solution. In addition, to investigate the adsorption and penetration of drug-nanocarrier complex into the cell membrane, well-tempered metadynamics simulations and steered molecular dynamics (SMD) simulations were performed. Based on the obtained results, it is evident that intermolecular hydrogen bonds (HBs) and π-π interactions play a significant role in expediting the interaction between drug molecules and the graphene oxide (GO) nanosheet, ultimately resulting in the formation of a stable SXR-GO complex. The Lennard-Jones (L-J) energy value for the interaction of SXR with GONF is calculated to be approximately -98.85 kJ/mol. In the SXR-GONF complex system, the dominant interaction between SXR and GONF is attributed to the L-J term, resulting from the formation of a strong π-π interaction between the drug molecules and the substrate surface. Moreover, our simulations show by decreasing the distance of GONF with respect to cell membrane, the interaction energy of GONF-membrane significantly decrease to -1500 kJ/mol resulting in fast diffusion of SXR-GONF complex toward the bilayer surface that is favored opening the way to natural drug nanocapsule.

Experimental and in silico evaluations of the possible molecular interaction between airborne particulate matter and SARS-CoV-2.

During the early stage of the COVID-19 pandemic (winter 2020), the northern part of Italy has been significantly affected by viral infection compared to the rest of the country leading the scientific community to hypothesize that airborne particulate matter (PM) could act as a carrier for the SARS-CoV-2. To address this controversial issue, we first verified and demonstrated the presence of SARS-CoV-2 RNA genome on PM2.5 samples, collected in the city of Bologna (Northern Italy) in winter 2021. Then, we employed classical molecular dynamics (MD) simulations to investigate the possible recognition mechanism(s) between a newly modelled PM2.5 fragment and the SARS-CoV-2 Spike protein. The potential molecular interaction highlighted by MD simulations suggests that the glycans covering the upper Spike protein regions would mediate the direct contact with the PM2.5 carbon core surface, while a cloud of organic and inorganic PM2.5 components surround the glycoprotein with a network of non-bonded interactions resulting in up to 4769 total contacts. Moreover, a binding free energy of -207.2 ± 3.9 kcal/mol was calculated for the PM-Spike interface through the MM/GBSA method, and structural analyses also suggested that PM attachment does not alter the protein conformational dynamics. Although the association between the PM and SARS-CoV-2 appears plausible, this simulation does not assess whether these established interactions are sufficiently stable to carry the virus in the atmosphere, or whether the virion retains its infectiousness after the transport. While these key aspects should be verified by further experimental analyses, for the first time, this pioneering study gains insights into the molecular interactions between PM and SARS-CoV-2 Spike protein and will support further research aiming at clarifying the possible relationship between PM abundance and the airborne diffusion of viruses.

Pharmacological and In Silico Analysis of Oat Avenanthramides as EGFR Inhibitors: Effects on EGF-Induced Lung Cancer Cell Growth and Migration.

Avena sativa L. is a wholegrain cereal and an important edible crop. Oats possesses high nutritional and health promoting values and contains high levels of bioactive compounds, including a group of phenolic amides, named avenanthramides (Avns), exerting antioxidant, anti-inflammatory, and anticancer activities. Epidermal growth factor receptor (EGFR) represents one of the most known oncogenes and it is frequently up-regulated or mutated in human cancers. The oncogenic effects of EGFR include enhanced cell growth, angiogenesis, and metastasis, and down-regulation or inhibition of EGFR signaling has therapeutic benefit. Front-line EGFR tyrosine kinase inhibitor therapy is the standard therapy for patients with EGFR-mutated lung cancer. However, the clinical effects of EGFR inhibition may be lost after a few months of treatment due to the onset of resistance. Here, we showed the anticancer activity of Avns, focusing on EGFR activation and signaling pathway. Lung cancer cellular models have been used to evaluate the activity of Avns on tumor growth, migration, EMT, and anoikis induced by EGF. In addition, docking and molecular dynamics simulations showed that the Avns bind with high affinity to a region in the vicinity of αC-helix and the DGF motif of EGFR, jeopardizing the target biological function. Altogether, our results reveal a new pharmacological activity of Avns as EGFR tyrosine kinase inhibitors.

Quantifying the Stability of the Hydronium Ion in Organic Solvents With Molecular Dynamics Simulations.

The solution-phase stability of the hydronium ion catalyst significantly affects the rates of acid-catalyzed reactions, which are ubiquitously utilized to convert biomass to valuable chemicals. In this work, classical molecular dynamics simulations were performed to quantify the stability of hydronium and chloride ions by measuring their solvation free energies in water, 1,4-dioxane (DIOX), tetrahydrofuran (THF), γ-valerolactone (GVL), N-methyl-2-pyrrolidone (NMP), acetone (ACE), and dimethyl sulfoxide (DMSO). By measuring the free energy for transferring a hydronium ion from pure water to pure organic solvent, we found that the hydronium ion is destabilized in DIOX, THF, and GVL and stabilized in NMP, ACE, and DMSO relative to water. The distinction between these organic solvents can be used to predict the preference of the hydronium ion for specific regions in aqueous mixtures of organic solvents. We then incorporated the stability of the hydronium ion into a correlative model for the acid-catalyzed conversion of 1,2-propanediol to propanal. The revised model is able to predict experimental reaction rates across solvent systems with different organic solvents. These results demonstrate the ability of classical molecular dynamics simulations to screen solvent systems for improved acid-catalyzed reaction performance.

A molecular dynamics simulation study decodes the early stage of the disassembly process abolishing the human SAMHD1 function.

The human sterile alpha motif SAM and HD domain-containing protein 1 (SAMHD1) restricts in non-cycling cells type the infection of a large range of retroviruses including HIV-1, reducing the intracellular pool concentration of deoxynucleoside triphosphates (dNTPs) required for the reverse transcription of the viral genome. The enzyme is in equilibrium between different forms depending on bound cofactors and substrate. In this work, two SAMHD1 three-dimensional models have been investigated through classical molecular dynamics simulation, to define the role of cofactors and metal ions in the association of the tetrameric active form. A detailed analysis of the inter-subunit interactions, taking place at the level of helix 13, indicates that removal of metal ions and cofactors induces an asymmetric loosening of the monomer-monomer interface leading to the formation of a loose tetramer where the two dimeric interfaces are weakened in different way.

Simulative and experimental investigation on the cleavage site that generates the soluble human LOX-1.

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a scavenger receptor that mediates the recognition, the binding and internalization of ox-LDL. A truncated soluble form of LOX-1 (sLOX-1) has been identified that, at elevated levels, has been associated to acute coronary syndrome. Human sLOX-1 is the extracellular part of membrane LOX-1 which is cleaved in the NECK domain with a mechanism that has not yet been identified. Purification of human sLOX-1 has been carried out to experimentally identify the cleavage site region within the NECK domain. Molecular modelling and classical molecular dynamics simulation techniques have been used to characterize the structural and dynamical properties of the LOX-1 NECK domain in the presence and absence of the CTLD recognition region, taking into account the obtained proteolysis results. The simulative data indicate that the NECK domain is stabilized by the coiled-coil heptad repeat motif along the simulations, shows a definite flexibility pattern and is characterized by specific electrostatic potentials. The detection of a mobile inter-helix space suggests an explanation for the in vivo susceptibility of the NECK domain to the proteolytic cleavage, validating the assumption that the NECK domain sequence is composed of a coiled-coil motif destabilized in specific regions of functional significance.