Molecular Dynamics and Metadynamics Insights of 1,4-Dioxane-Induced Structural Changes of Biomembrane Models.

1,4-Dioxane is a cytotoxic B2-type human carcinogen, a serious water pollutant produced solely by industrial activity. The effect of 1,4-dioxane on phospholipid membrane models composed of dipalmitoyl-phosphatidylcholine (DPPC) and its branched isomer (isodipalmitoyl-phosphatidylcholine, IPPC) was investigated using MD simulations. Clear and polluted membranes were compared by membrane parameters such as area per lipid (APL), volume per lipid (VPL), compressibility modulus, membrane thickness, and orderliness of lipid tails. While neat systems significantly differ from each other, the presence of the pollutant has the same effect on both types of lipid membranes. High density of dioxane appears in the vicinity of ester groups, which pushes away lipid headgroups from each other, leading to an overall change in lipid structure: APL and VPL grows, while the orderliness of lipid tails, membrane thickness, and compressibility modulus decrease. Orientational preferences of water and dioxane molecules were also investigated and different membrane regions have been specified according to the stance of water molecules. Free-energy profile for 1,4-dioxane penetration mechanism into DPPC membranes was carried out using metadynamics for two different concentrations of the pollutant (c1 = 7.51 g/dm3, c2 = 75.10 g/dm3), which showed that the higher the concentration is, the lower the free energy of penetration gets. Only a small free-energy barrier was found in the headgroup region and accumulation of dioxane is thermodynamically unfavored in the middle of the bilayer. The penetration mechanism has been described in detail based on the orientational preference of 1,4-dioxane molecules and the free-energy profiles.

Serum N-Glycosylation in Parkinson's Disease: A Novel Approach for Potential Alterations.

In this study, we present the application of a novel capillary electrophoresis (CE) method in combination with label-free quantitation and support vector machine-based feature selection (support vector machine-estimated recursive feature elimination or SVM-RFE) to identify potential glycan alterations in Parkinson's disease. Specific focus was placed on the use of neutral coated capillaries, by a dynamic capillary coating strategy, to ensure stable and repeatable separations without the need of non-mass spectrometry (MS) friendly additives within the separation electrolyte. The developed online dynamic coating strategy was applied to identify serum N-glycosylation by CE-MS/MS in combination with exoglycosidase sequencing. The annotated structures were quantified in 15 controls and 15 Parkinson's disease patients by label-free quantitation. Lower sialylation and increased fucosylation were found in Parkinson's disease patients on tri-antennary glycans with 2 and 3 terminal sialic acids. The set of potential glycan alterations was narrowed by a recursive feature elimination algorithm resulting in the efficient classification of male patients.

An Ab Initio Investigation of the 4,4'-Methlylene Diphenyl Diamine (4,4'-MDA) Formation from the Reaction of Aniline with Formaldehyde.

The most commonly applied industrial synthesis of 4,4'-methylene diphenyl diamine (4,4'-MDA), an important polyurethane intermediate, is the reaction of aniline and formaldehyde. Molecular understanding of the 4,4'-MDA formation can provide strategy to prevent from side reactions. In this work, a molecular mechanism consisted of eight consecutive, elementary reaction steps from anilines and formaldehyde to the formation of 4,4'-MDA in acidic media is proposed using accurate G3MP2B3 composite quantum chemical method. Then G3MP2B3-SMD results in aqueous and aniline solutions were compared to the gas phase mechanism. Based on the gas phase calculations standard enthalpy of formation, entropy and heat capacity values were evaluated using G3MP2B3 results for intermediates The proposed mechanism was critically evaluated and important side reactions are considered: the competition of formation of protonated p-aminobenzylaniline (PABAH⁺), protonated aminal (AMH⁺) and o-aminobenzylaniline (OABAH⁺). Competing reactions of the 4,4'-MDA formation is also thermodynamically analyzed such as the formation of 2,4-MDAH⁺, 3,4-MDAH⁺. AMH⁺ can be formed through loose transition state, but it becomes kinetic dead-end, while formation of significant amount of 2,4-MDA is plausible through low-lying transition state. The acid strength of the key intermediates such as N-methylenebenzeneanilium, PABAH⁺, 4-methylidenecyclohexa-2,5-diene-1-iminium, and AMH⁺ was estimated by relative pKa calculation.