Ortho-Methoxy Group as a Mild Inhibitor of the Reactions Between Carboxylic Acid and Phenols

According to the current database of natural products, over 25,000 compounds contain a vanillyl ring in their structure. The reasoning behind the high occurrence of the vanillyl ring structure seemed to be poorly understood, specifically the preference for a methoxy-substituted phenol structure as opposed to its dihydroxy analogue. To better understand this, we investigated the reaction mechanisms of two methoxyphenol structures, in syn and anti conformations, two hydroxyphenol structures, also in syn and anti conformations, and phenol as a reference structure, with acetic acid. Of the starting structures, the syn hydroxyphenol was found to be kinetically the most reactive, and formed the most stable product, while both hydroxyl-substituted phenols reacted more favorably with acetic acid than the methoxyphenols. A preference for the methoxyphenol molecule may exist as a way to hinder the formation of stable covalent bonds between natural products and cellular components. This work is licensed under a Creative Commons Attribution 4.0 International License

Navigating protein landscapes with a machine-learned transferable coarse-grained model

The most popular and universally predictive protein simulation models employ all-atom molecular dynamics (MD), but they come at extreme computational cost. The development of a universal, computationally efficient coarse-grained (CG) model with similar prediction performance has been a long-standing challenge. By combining recent deep learning methods with a large and diverse training set of all-atom protein simulations, we here develop a bottom-up CG force field with chemical transferability, which can be used for extrapolative molecular dynamics on new sequences not used during model parametrization. We demonstrate that the model successfully predicts folded structures, intermediates, metastable folded and unfolded basins, and the fluctuations of intrinsically disordered proteins while it is several orders of magnitude faster than an all-atom model. This showcases the feasibility of a universal and computationally efficient machine-learned CG model for proteins

Energetics of π-π Stacking Interactions: Implications in the Phase Separation of Intrinsically Disordered Proteins

π-π stacking interactions are found throughout the proteome and have been shown to play a role in the liquid-liquid phase separation of intrinsically disordered proteins; however, the structural and energetic properties of π-π interactions that drive intra- and intermolecular protein interactions are poorly understood. In this study, we investigate the pairwise interactions of sp2-hybridized groups within proteins through an analysis of the Protein Data Bank. Along with these statistical data, small-molecule representations of these groups are simulated using molecular dynamics, while quantum mechanical and molecular mechanical calculations are used to characterize the energies of π-π interactions across their conformational distributions. Molecular dynamics is further used to simulate the folding and unfolding equilibria of small peptides enriched in sp2 groups. Ultimately, this study provides a thorough quantification of the energetics of π-stacking contacts in proteins and evaluates the strengths and limitations of different computational methods in accurately modelling these interactions.M.Sc

Sugars in Space: A Quantum Chemical Study on the Barrierless Formation of Dihydroxyacetone in the Interstellar Medium

Among many theories on the life’s origins, regions between star systems in a galaxy is hypothesized to provide prebiotic material on Earth. Simple sugars, including glycolaldehyde, are confirmed to exist in interstellar medium (ISM) and can be intermediates in the formose reaction to form dihydroxyacetone or DHA. In the studied segment of the formose reaction, hydroxy carbene is sequentially added to formaldehyde, forming glycolaldehyde (hydroxyacetaldehyde) after the first addition and glycerone in the second. The proposed theoretical mechanism was validated through quantum chemical calculations. An exothermic and exergonic pathway favourable in ISM conditions was found, giving a possible explanation for glycerone formation. The products in question participates in biological processes like energy production, the phosphorylated form of glycerone, DHA-P, participates in glycolysis, and energy storage while glycerone is the source of the glycerine backbone in lipids. The studied reaction is a segment of the formose reaction and further polymerization can lead to pentose and hexose, which take part in the formation of RNA and DNA. Hence, this research explores the hypothesis of exogenous production and delivery of prebiotic material to Earth, building up to the conditions allowing the formation of rudimentary lifeforms.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Formation of Acetamide in Interstellar Medium

Acetamide (C2H5NO) is the largest molecule containing a peptide bond, which is an amine (-NH2) group bonded to a carbonyl (C = O) group, that has yet been detected in interstellar medium (ISM). It is also considered to be a precursor for amino acids (the building blocks of proteins). Formation of acetamide in ISM is believed to occur due based on evidence for the existence of the molecule itself and its component smaller species in ISM. A case study of acetamide is presented here, to introduce a new method to determine its possible formation reaction pathways in ISM based on the molecular formula of a species. All possible species with the same molecular formula as acetamide (C2H5NO) but with different connectivity, the so-called constitutional isomers of the molecule (198 structures, 91 unique species), were created and studied under the extreme conditions of dense molecular clouds. Acetamide was found to be the most stable of the C2H5NO isomer family. Based on the stability of the uni- and bimolecular species, eight reactions were proposed which could led to the formation of acetamide in ISM

Oxidatively-mediated in silico epimerization of a highly amyloidogenic segment in the human calcitonin hormone (hCT15-19)

In order to study the effects of peptide exposure to oxidative attack, we chose a model reaction in which the hydroxyl radical discretely abstracts a hydrogen atom from the α-carbon of each residue of a highly amyloidogenic region in the human calcitonin hormone, hCT15-19. Based on a combined Molecular Mechanics / Quantum Mechanics approach, the extended and folded L- and D-configuration and radical intermediate hCT15-19 peptides were optimized to obtain their compactness, secondary structure and relative thermodynamic data. The results suggest that the epimerization of residues is generally an exergonic process that can explain the cumulative nature of molecular aging. Moreover, the configurational inversion induced conformational changes can cause protein dysfunction. The epimerization of the central residue to the D-configuration induced a hairpin structure in hCT15-19, concomitant with a possible oligomerization of human calcitonin into Aβ(1–42)-like amyloid fibrils present in patients suffering from Alzheimer’s disease