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1,1-Diamino-2,2-dinitroethene (FOX-7) is an energetic material with low sensitivity and high detonation performance, thus it has been considered as a potential replacement for traditional nitro-based energetic materials. In a recent...

A protocol that accurately assesses the intestinal permeability of small molecule compounds plays an essential role in decreasing the cost and time in inventing a new drug. This manuscript presents a novel computational method to study the passive permeation of small molecule drugs based on the inhomogeneous solubility-diffusion model. The multidimensional free energy surface of the drug transiting through a lipid bilayer is computed with transition-tempered metadynamics that accurately captures the mechanisms of passive permeation. The permeability is computed by following the diffusion motion of the drug molecules along the minimal free energy path found on the multidimensional free energy surface. This computational method is assessed by studying the permeability of five small molecule drugs (ketoprofen, naproxen, metoprolol, propranolol, and salicylic acid). The results demonstrate a remarkable agreement between the computed permeabilities and those measured with the intestinal assay. The in silico method reported in this manuscript also reproduces the permeability measured from the intestinal assay (in vivo) better than the cell-based assays (e.g., PAMPA and Caco-2) do. In addition, the multidimensional free energy surface reveals the interplay between the structure of the small molecule and its permeability, shedding light on strategies of drug optimization.

With an increasing prevalence of electronic cigarette (e-cigarette) use, especially among youth, there is an urgent need to better understand the biological risks and pathophysiology of health conditions related to e-cigarettes. A majority of e-cigarette aerosols are in the submicron size and would deposit in the alveolar region of the lung, where they must first interact with the endogenous pulmonary surfactant. To date, little is known whether e-cigarette aerosols have an adverse impact on the pulmonary surfactant. We have systematically studied the effect of individual e-cigarette ingredients on an animal-derived clinical surfactant preparation, bovine lipid extract surfactant, using a combination of biophysical and analytical techniques, including in vitro biophysical simulations using constrained drop surfactometry, molecular imaging with atomic force microscopy, chemical assays using carbon nuclear magnetic resonance and circular dichroism, and in silico molecular dynamics simulations. All data collectively suggest that flavorings used in e-cigarettes, especially menthol, play a predominant role in inhibiting the biophysical function of the surfactant. The mechanism of biophysical inhibition appears to involve menthol interactions with both phospholipids and hydrophobic proteins of the natural surfactant. These results provide novel insights into the understanding of the health impact of e-cigarettes and may contribute to a better regulation of e-cigarette products.

The interaction between α-synuclein (α-syn) and synaptic vesicles (SVs) plays an important role in the life cycle of α-syn, and a disruption of it could lead to numerous neurodegenerative diseases. The N-terminal of α-syn (first 15 residues) has been shown to recapitulate the association dynamics of α-syn to the bilayer in various studies. This manuscript presents an extensive all-atom molecular dynamics studies (close to 100 μs) of the interaction between the N-terminal of α-syn and a lipid bilayer that mimics the SV under physiological conditions. The research demonstrates α-syn’s overwhelming binding preference to the outer leaflet of the SV, which carries a net negative charge as compared to the neutral inner leaflet. Further structural analysis reveals that the Coulombic interaction between the positively charged residues of α-syn and the negatively charged lipid surface is the driving force of the binding, but has a potential of hindering the configurational change of α-syn. In addition, metadynamics simulations are carried out to investigate the folding of the N-terminal of α-syn in the presence and absence of the lipid bilayer, and the result confirms that the α-syn/membrane association facilitates protein folding.