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Introduction: Staph infection, caused by a bacterium known as Staphylococcus aureus, results in a range of diseases from cellulitis to meningitis. Dicoumarol compounds are now emerging as new anti-Staph infection agents as they possess a different chemical structure than compounds used in previous treatments, in order to combat antibiotic-resistant strains. However, it is unclear how such chemical modulations to the dicoumarol backbone structure achieve higher drug performance. Methods: The following review analyzed various quantitative structure-activity relationship (QSAR) studies on dicoumarol compounds and compared them against the corresponding minimum inhibitory concentration and binding affinity values. Results: Compared to the antimicrobial activity, the dicoumarol derivatives with electron withdrawing substituents, CL, NO2, and CF3 showed an inverse correlation; whereas, the opposite was observed with electron donating compounds such as OH, OMe, and amine groups. Based on the interactions of dicoumarol at the active site, an “aromatic donor-acceptor” relationship was proposed as the method of action for this drug. Furthermore, substituent positioning on the benzene ring was found to exert a greater effect on the binding affinity, speculating that the mechanism of action is two characteristics based, needing, both, the proper aromatic pi-pi interaction for stabilization and direct binding to the OH group in the Tyrosine residue, affected by the steric hindrance. Conclusion: This foundational review can enhance productivity sought by the pharmaceutical agency to use combinational chemistry to increase the efficiency to discover new hits in the synthesis of dicoumarol drugs against Staph infection.

We inhale oxygen to produce energy by oxidizing our food. However, almost 10% of the inhaled oxygen is escaped that basic route, and start to oxidize our bodies. This phenomenon referred to as “oxidatve stress”. This, chemical stress, can be reduced, by higher Vitamin C concentraton. Those who sport will inhale more oxygen and consequently, they have even higher “oxidatve stress” and need substantally higher Vitamin C concentraton. Since Vitamin C is not a drug, but only strengthening the human body, therefore, there is no danger if, for the sake of success, we take more Vitamin C, than, absolutely, necessary.

In this paper, we present an additional, new cage-GABA compound, called 4-amino-1-(4′-dimethylaminoisopropoxy-5′,7′-dinitro-2′,3′-dihydro-indol-1-yl)-1-oxobutane-γ-aminobutyric acid (iDMPO-DNI-GABA), and currently, this compound is the only photoreagent, which can be applied for GABA uncaging without experimental compromises. By a systematic theoretical design and successful synthesis of several compounds, the best reagent exhibits a high two-photon efficiency within the 700–760 nm range with excellent pharmacological behavior, which proved to be suitable for a complex epileptic study. Quantum chemical design showed that the optimal length of the cationic side chain enhances the two-photon absorption by 1 order of magnitude due to the cooperating internal hydrogen bonding to the extra nitro group on the core. This feature increased solubility while suppressing membrane permeability. The efficiency was demonstrated in a systematic, wide range of in vitro single-cell neurophysiological experiments by electrophysiological as well as calcium imaging techniques. Scalable inhibitory ion currents were elicited by iDMPO-DNI-GABA with appropriate spatial–temporal precision, blocking both spontaneous and evoked cell activity with excellent efficiency. Additionally, to demonstrate its applicability in a real neurobiological study, we could smoothly and selectively modulate neuronal activities during artificial epileptic rhythms first time in a neural network of GCaMP6f transgenic mouse brain slices.

Background: Peptide bonds are among the fundamental building blocks of life, polymerizing amino acids to form proteins that make up the structural components of living cells and regulate biochemical processes. The detection of glycine by NASA in comet Wild 2 in 2009 suggests the possibility of the formation of biomolecules in extraterrestrial environments through the interstellar medium. Detected in the dense molecular cloud Sagittarius B2, acetamide is the largest molecule containing a peptide bond and is hypothesized to be the precursor to all amino acids; as such, viability of its formation is of important biological relevance. Methods: Under a proposed mechanism of ammonia and ketene reactants, which have also been detected in dense molecular clouds in the ISM, the reaction pathway for the formation of acetamide was modelled using quantum chemical calculations in Gaussian16, using Austin-Frisch-Petersson functional with dispersion density functional theory at a 6-31G(d) basis set level of theory to optimize geometries and determine the thermodynamic properties for the reaction. Stability of the reactants, transition states, and products were examined to establish a reasonable mechanism. Conclusion: Product formation of acetamide was found to be highly exergonic and exothermic with a low energy barrier, suggesting a mechanism that is viable in the extreme density and temperature conditions found in ISM.

Background: Many observational studies have found the presence of organic molecules in interstellar medium (ISM) via spectroscopy. NH2CONH2 (urea) was first detected in ISM in 2014. Containing two NH2 groups, urea is an important biological molecule in metabolism as a carrier for waste nitrogen. The discovery of urea in ISM suggests the possibility of the formation of other biomolecules which contain peptide bonds, such as proteins. This supports the origin of life theory proposing that these biomolecules were initially formed in space and later arrived to Earth. Methods: This study investigates two possible reaction pathways for the formation of protonated urea (ureaH+) in dense molecular clouds via molecules previously observed in the ISM, formamide (HCONH2) and protonated hydroxylamine (NH2OH2+). The thermodynamics and optimized geometries were calculated for the final steps of the formation of ureaH+ using Gaussian16 at the APFD/6-31G(d,p) level of theory and a transition state was confirmed. Results: The overall mechanism, as well as the studied proton rearrangement of an intermediate to ureaH+, were found to be exothermic and exergonic processes. Conclusion: From the calculations, the conditions of ISM provide an adequate environment for the formation of ureaH+ and urea.

Herein we comparatively comment on the molecular metric ‘amidicity’, a descriptor of amide reactivity, and differing methods to determining it; with focus on lactam-rings. Specifically, our established amidicity percentage (AM%) approach is quantitatively contrasted with the transamidation (TA) method. This comment is organised into two sections, firstly addressing the differing methods in context of the computational bases of amidicity. This is followed by the quantitative demonstration that although both the AM% and HRS methods provide estimates of resonance enthalpy (ΔHRE), the former is more reliable across a wider set of systems. The robustness of the AM% approach is affirmed by quantitative matching of experimental NMR and kinetics measurements tracking changes in amide reactivities, including in Penicillin arising from modulation of its amide group and environmental effects.

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.

Finding a relationship on how a three-dimensional protein folds from its linear amino acid chain gets more complex with increasing chain length, so working on a smaller peptide conformational problem can provide initial ideas on what are the main molecular forces and how these influence the folding process. Following the study of conformations of amino acid units entering the proteins to understand the secondary structure of small peptides, this paper proposes mathematical models for the several two-rotor cross-sections of the five-dimensional N-acetyl-glycyl-glycine-N′-methylamide potential energy hypersurface (PEHS). These cross-sections are extracted along the first glycine subunit, with its coordinates fixed at the five energy minima of the glycine diamide. The resulting mathematical models yield an average RMSE of 1.36 kJ mol−1 and an average R2 of 0.9923 with respect to energy values obtained from DFT calculations. The minima geometries obtained from these models are also in good agreement with DFT-optimized energy minima conformers. An important aspect of this study also tackles the relationship between the PEHS of the glycyl-glycine diamide and its glycine subunits. It has been observed that there are deviations up to 28.35 kJ mol−1 and 29.52 kJ mol−1 between the PEHS cross-sections along γL and γD conformations, respectively, in the first glycine subunit. This may suggest that there are significant backbone–backbone intermolecular forces acting on the dipeptide. The abovementioned findings can help in developing more complex mathematical models for polypeptide folding from amino acid subunits.

In the polyurethane industry, the undesirable dimerization and oligomerization of methylene diphenyl diisocyanate (MDI) are unwanted and problematic phenomena. The relative ratios of these dimers and oligomers have a strong temperature dependence, and they can be formed below and above the melting point of MDI (316.15 K). All possible structures of the isomers and their dimers were optimized, and then their thermodynamic functions were calculated at the M06-2X/6-31(d,p) level of theory. The dimerization of isocyanate groups can result in four-, five-, and six-membered rings. The four-membered ring is the most stable one due to the aromatic electrons in π orbitals of the uretidione ring. The relative stability of the dimers is therefore influenced by the steric effects and the relative positions of isocyanate groups. The most stable dimer is the one which is formed from the reaction of the p,o- and o,p-MDI isomers due to their intrinsic interactions, which were classified, and their impact on dimer stability was discussed.

Predicting the three-dimensional structure of a protein from its amino acid sequence requires a complete understanding of the molecular forces that influences the protein folding process. Each possible conformation has its corresponding potential energy, which characterizes its thermodynamic stability. This is needed to identify the primary intra- and inter-molecular interactions, so that we can reduce the dimensionality of the problem, and create a relatively simple representation of the system. Investigating this problem using quantum chemical methods produces accurate results; however, this also entails large computational resources. In this study, an improved two-rotor potential energy function is proposed to represent the backbone interactions in amino acids through a linear combination of a Fourier series and a mixture of Gaussian functions. This function is applied to approximate the 20 amino acid diamide Ramachandran-type PESs, and results yielded an average RMSE of 2.36 kJ mol−1, which suggest that the mathematical model precisely captures the general topology of the conformational potential energy surface. Furthermore, this paper provides insights on the conformational preferences of amino acid diamides through local minima geometries and energy ranges, using the improved mathematical model. The proposed mathematical model presents a simpler representation that attempts to provide a framework on building polypeptide models from individual amino acid functions, and consequently, a novel method for rapid but accurate evaluation of potential energies for biomolecular simulations.

The conformational potential energy surface (PES) of a molecule provides insights into the relative stability of the possible foldamers. However, the time and space complexity of electronic structure calculations, commonly used to generate PES, increases exponentially with an increasing number of atoms. The use of mathematical functions to model the topology of conformational PES is an alternative to more computer-intensive quantum chemical calculations, but the choice and complexity of functions used are crucial in achieving more accurate results. This paper presents a method to illustrate the topology of amino acid diamide PESs through a linear combination of a Fourier series and a mixture of Gaussian functions. Results yield a significantly small error, with an average RMSE of 4.9946 kJ mol−1 for all fits, which suggest that these functions may be used to represent the topology of the PESs, with around twofold order of magnitude decrease in computational time, with respect to DFT electronic structure calculations. This study ultimately aims to provide a foundation for a framework on building polypeptide PES from individual amino acid PESs.

Carbon dioxide can be converted into fine chemicals such as methanol and thus, the produced renewable energy can be stored in chemical bonds through reductions. To achieve this, a water enhanced mechanism of CO2 hydrogenation leading to methanol has been designed by applying 1:3 (CO2 + 3H2) extended with a water molecule and a hydronium. The thermodynamic properties of the intermediate species and transition states have been calculated by using the W1U composite method. The energy efficiency of the studied mechanism is 27.1%. By understanding the mechanism, special purpose catalysts can be designed to accelerate carbon dioxide conversion.

Polycyclic aromatic hydrocarbons (PAH) are harmful chemicals emitted to the environment by incomplete combustion. As the aromatic structure grows, the carcinogenic effect increases, and thus, to understand their formation mechanisms is crucial. In this work, new reaction pathways leading to benzo(a)pyrene, a PAH with well-known carcinogenic effects, were explored by using DFT methods. Starting from chrysene or benzo(a)anthracene, three types of reaction mechanism were studied: hydrogen abstraction acetylene addition (HACA), hydrogen abstraction ethynyl radical addition (HAERA) and Diels-Alder (DA) processes. HAERA was the most and DA was the least exergonic. A deeper understanding of benzo(a)pyrene formation achieved.

Complex formation ability and stability of both weak and super-weak acids was studied by mean of in silico determined thermodynamic data of the complexes. While weak acids act like Bronsted acids forming hydrogen bond type Bronsted complexes, super-weak acids form Lewis complexes via van der Waals interaction. Unlike in the former type, upon complexation, C-H distances changes insignificantly, yet the complex formation is energy driven in the terms of zero-point corrected Energies, ΔE zp

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, hCT

In order to improve the fluorescence properties of the green fluorescent protein chromophore, p‑HOBDI ((5‑(4‑hydroxybenzylidene)‑2,3‑dimethyl‑3,5‑dihydro‑4H‑imidazol‑4‑one), sixteen dihydroimidazolone derivates were synthesized from thiohydantoin and arylaldehydes. The synthesis developed is an efficient, novel, one-pot procedure. The study provides a detailed description of the spectroscopic characteristics of the newly synthesized compounds, using p‑HOBDI as a reference. The new compounds all exhibited significantly stronger fluorescence than p‑HOBDI, up to 28 times higher quantum yields. An experimental and theoretical investigation of the relationship of the fluorescence properties with the molecular structure was also carried out. A good correlation was found between the emission wavenumber and the Hammett constant of the functional group, which suggests the intermolecular charge transfer (ICT) mechanism between the aromatic groups.

The global minimum (GM) structure of opiorphin (QRFSR) and its seven derivatives (qRFSR, QrFSR, QRfSR, QRFsR, QRFSr, QRYSR, QRySR) were explored using molecular mechanics method. Based on STRIDE analysis, most of the conformers possessed no secondary structures. Among global minima, only QrFSR epimer contained a β-turn formed between glutamine (Q1) and serine (S4) residues. The most common hydrogen bonds were formed between the 2nd arginine (R2) and glutamine (Q1) which also appeared in some GMs. According to DFT calculations (ωB97X-D/cc-pVTZ//B3LYP/6-31G(d)), the overall epimerization of the GM structures is a downhill process in the presence of an OH/H2O2 redox system.

Two-photon (TP) uncaging of neurotransmitter molecules is the method of choice to mimic and study the subtleties of neuronal communication either in the intact brain or in slice preparations. However, the currently available caged materials are just at the limit of their usability and have several drawbacks. The local and focal nature of their use may for example be jeopardized by a high spontaneous hydrolysis rate of the commercially available compounds with increased photochemical release rate. Here, using quantum chemical modelling we show the mechanisms of hydrolysis and two-photon activation, and synthesized more effective caged compounds. Furthermore, we have developed a new enzymatic elimination method removing neurotransmitters inadvertently escaping from their compound during experiment. This method, usable both in one and two-photon experiments, allows for the use of materials with an increased rate of photochemical release. The efficiency of the new compound and the enzymatic method and of the new compound are demonstrated in neurophysiological experiments.

© 2017 Elsevier B.V. The conformational space of β-turns of Ala-Gly dipeptide is analyzed theoretically using quantum mechanical methods. A number of potential minima are obtained and characterized. The potential energy surface suggests that β-turn conformers are susceptible to rapid radical formation, which leads to potential L and D epimerization. The calculated thermodynamics show that the radical mediated epimerization is possible and that the estimated barrier height for hydrogen abstraction on the Cα is the lowest for the Gly residue.

Glycine (Gly) residues are particularly susceptible to hydrogen abstraction; which results in the formation of the capto-dative stabilized Cα-centered Gly radical (GLR) on the protein backbone. We examined the effect of GLR formation on the structure of the Trp cage; tryptophan zipper; and the villin headpiece; three fast-folding and stable miniproteins; using all-atom (OPLS-AA) molecular dynamics simulations. Radicalization changes the conformation of the GLR residue and affects both neighboring residues but did not affect the stability of the Trp zipper. The stability of helices away from the radical center in villin were also affected by radicalization; and GLR in place of Gly15 caused the Trp cage to unfold within 1 µs. These results provide new evidence on the destabilizing effects of protein oxidation by reactive oxygen species.

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.

We examined the effects of Cα-centered radical formation on the stability of a model helical peptide, N-Ac-KK(AL)10KK-NH2. Three, 100 ns molecular dynamics simulations using the OPLS-AA force field were carried out on each α-helical peptide in six distinct binary TIP4P water/2,2,2-trifluoroethanol (TFE) mixtures. The α-helicity was at a maximum in 20% TFE, which was inversely proportional to the number of H-bonds between water molecules and the peptide backbone. The radial distribution of TFE around the peptide backbone was highest in 20% TFE, which enhanced helix stability. The Cα-centered radical initiated the formation of a turn within 5 ns, which was a smaller kink at high TFE concentrations, and a loop at lower TFE concentrations. The highest helicity of the peptide radical was measured in 100% TFE. The formation of hydrogen bonds between the peptide backbone and water destabilized the helix, whereas the clustering of TFE molecules around the radical center stabilized the helix. Following radical termination, the once helical structure converted to a β-sheet rich state in 100% water only, and this transition did not occur in the nonradical control peptide. This study gives evidence on how the formation of peptide radicals can initiate α-helical to β-sheet transitions under oxidative stress conditions.

The oxidation of polyunsaturated hydrocarbons by ·OH radical can play an important role in lipid oxidation of polyunsaturated fatty acids (PUFA) such as arachidonic acid (AA). As a prototype of this oxidation, the reaction of 1,4-pentadiene with the ·OH radical is studied using the QCISD(T)/cc-pVTZ//BH&HLYP/6-31G(d) level of theory. One of the prereaction complexes is shown to be a springboard for the indirect bisallylic hydrogen abstraction (AO), terminal (T0O), and nonterminal ·OH addition (NT0O) reactions. The enthalpies of the transition states of the AO, T0O, and NT0O reactions are found to be lower than those of the reactants, so all these reactions are expected to be fast. The nonterminal adduct is found to be reactive via two low-lying consecutive reaction channels. The first channel is a five-membered ring closing (NT1O). The second channel is bond scission, which results in an allyl radical and a vinyl alcohol (NT2O). An analogous reaction pathway in which AA takes the place of 1,4-pentadiene was explored using the ONIOM(QCISD(T)/cc-pVTZ:BH&HLYP/6-31G(d))//BH&HLYP/6-31G(d) method. The results show that the formation of the five-membered ring (AA-NT1O) is energetically favored. Our results demonstrate for the first time a possible, ab initio-based mechanism for the nonenzymatic biosynthesis of isoprostane-like structures from AA without the presence of molecular oxygen. Furthermore, the energetically low-lying bond scission channel may explain the observed formation of short fatty acids and dieneols (tautomers of unsaturated aldehydes).