In this article we report a combined experimental and computational study concerning the effects of deuteration on the binding of histamine and two other histaminergic agonists to 3H-tiotidine-labeled histamine H2 receptor in neonatal rat astrocytes. Binding affinities were measured by displacing radiolabeled tiotidine from H2 receptor binding sites present on cultured neonatal rat astrocytes. Quantum-chemical calculations were performed by employing the empirical quantization of nuclear motion within a cluster model of the receptor binding site extracted from the homology model of the entire H2 receptor. Structure of H2 receptor built by homology modelling is attached in the supporting information (S1 Table) Experiments clearly demonstrate that deuteration affects the binding by increasing the affinity for histamine and reducing it for 2-methylhistamine, while basically leaving it unchanged for 4-methylhistamine. Ab initio quantum-chemical calculations on the cluster system extracted from the homology H2 model along with the implicit quantization of the acidic N–H and O–H bonds demonstrate that these changes in the binding can be rationalized by the altered strength of the hydrogen bonding upon deuteration known as the Ubbelohde effect. Our computational analysis also reveals a new mechanism of histamine binding, which underlines an important role of Tyr250 residue. The present work is, to our best knowledge, the first study of nuclear quantum effects on ligand receptor binding. The ligand H/D substitution is relevant for therapy in the context of perdeuterated and thus more stable drugs that are expected to enter therapeutic practice in the near future. Moreover, presented approach may contribute towards understanding receptor activation, while a distant goal remains in silico discrimination between agonists and antagonists based on the receptor structure.

Monoamine oxidase (MAO) enzymes catalyze the degradation of a very broad range of biogenic and dietary amines including many neurotransmitters in the brain, whose imbalance is extensively linked with the biochemical pathology of various neurological disorders. Although sharing around 70 % sequence identity, both MAO A and B isoforms differ in substrate affinities and inhibitor sensitivities. Inhibitors that act on MAO A are used to treat depression, due to their ability to raise serotonin concentrations, whereas MAO B inhibitors decrease dopamine degradation and improve motor control in patients with Parkinson disease. Despite this functional importance, the factors affecting MAO selectivity are poorly understood. Here, we used a combination of molecular dynamics (MD) simulations, molecular mechanics with Poisson-Boltzmann and surface area solvation (MM-PBSA) binding free energy evaluations, and quantum mechanical (QM) cluster calculations to address the unexpected, yet challenging MAO B selectivity for N-methylhistamine (NMH) over histamine (HIS), differing only in a single methyl group distant from the reactive ethylamino center. This study shows that a dominant selectivity contribution is offered by a lower activation free energy for NMH by 2.6 kcal mol , in excellent agreement with the experimental ΔΔG =1.4 kcal mol , together with a more favorable reaction exergonicity and active-site binding. This study also confirms the hydrophobic nature of the MAO B active site and underlines the important role of Ile199, Leu171, and Leu328 in properly orienting substrates for the reaction.

Metal complexes with ML or ML2 stoichiometry have been isolated in the reaction of Zn(NO3)2, ZnBr2 or M(NO3)2/NaBF4, M = Zn(ii), Co(ii) or Ni(ii), with either amino acid or amine substituted tridentate nitrogen ligands based on bis(2-picolyl)amine (bpa) or bis(2-quinaldyl)amine (bqa). The stoichiometry (M : L = 1 : 1 or 1 : 2) and stereochemistry (mer, trans-fac or cis-fac) of the products have been studied by NMR and IR spectroscopy, X-ray single crystal analysis and quantum-chemical calculations with an implicit SMD solvation model.

Supramolecular ionogels were prepared by the gelation of room-temperature ionic liquid 1-butyl-3-methylimidazolium tetrafluoroborate ([BMIm][BF4 ]) with (S,S)-bis(leucinol)oxalamide. Remarkably, the ionic conductivity of solutions and ionogels with low gelator concentrations is higher than that of neat [BMIm][BF4 ]. On the basis of molecular dynamics simulations and quantum mechanical calculations, the origin of this phenomenon is attributed to the higher affinity of gelator molecules towards [BF4 ](-) ions, which reduces the electrostatic attraction between [BMIm](+) and [BF4 ](-) and thus increases their mobility. With increasing gelator concentration, the ionic conductivity decreases due to the formation of a denser gelator matrix, which hinders the pathways for ionic transport. However, even for very dense ionogels, this decrease is less than one order of magnitude relative to neat [BMIm][BF4 ], and thus they can be classified as highly conductive materials with strong potential for application as functional electrolytes.

Pyridine substituted with one and two bicyclic guanidine groups has been studied as a potential source of superbases. 2-{hpp}C5H4N (I) and 2,6-{hpp}2C5H3N (II) (hppH = 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine) were protonated using [HNEt3][BPh4] to afford [I-H][BPh4] (1a), [II-H][BPh4] (2), and [II-H2][BPh4]2 (3). Solution-state (1)H and (15)N NMR spectroscopy shows a symmetrical cation in 2, indicating a facile proton-exchange process in solution. Solid-state (15)N NMR data differentiates between the two groups, indicating a mixed guanidine/guanidinium. X-ray diffraction data are consistent with protonation at the imine nitrogen, confirmed for 1a by single-crystal neutron diffraction. The crystal structure of 1a shows association of two [I-H](+) cations within a cage of [BPh4](-) anions. Computational analysis performed in the gas phase and in MeCN solution shows that the free energy barrier to transfer a proton between imino centers in [II-H](+) is 1 order of magnitude lower in MeCN than in the gas phase. The results provide evidence that linking hpp groups with the pyridyl group stabilizes the protonation center, thereby increasing the intrinsic basicity in the gas phase, while the bulk prevents efficient cation solvation, resulting in diminished pKa(MeCN) values. Spectrophotometrically measured pKa values are in excellent agreement with calculated values and confirm that I and II are superbases in solution.

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Amazonian wildfires in 2019 have raised awareness about rainforest burning due to increased emissions of particulate matter and carbon. In the context of these emissions, by-products of lignin thermal degradation (i.e. methoxyphenols) are often neglected. Methoxyphenols entering the atmosphere may form intermediates with currently unknown reaction mechanisms and toxicity. This study for the first time provides a comprehensive insight into the impact of lignin degradation products [guaiacol, catechol], and their nitrated intermediates [4-nitrocatechol, 4,6-dinitroguaiacol, 5-nitroguaiacol] on zebrafish Danio rerio. Results revealed 4-nitrocatechol and catechol as the most toxic, followed by 4,6DNG > 5NG > GUA. The whole-organism bioassay integrated with molecular modeling emphasized the potential of methoxyphenols to inhibit tyrosinase, lipoxygenase, and carbonic anhydrase, consequently altering embryonic development (i.e. affected sensorial, skeletal, and physiological parameters, pigmentation formation failure, and non-hatching of larvae). The whole-organism bioassay integrated with in silico approach confirmed the harmful effects of lignin degradation products and their intermediates on aquatic organisms, emphasizing the need for their evaluation within ecotoxicity studies focused on aquatic compartments.

SrLip is an extracellular enzyme from Streptomyces rimosus (Q93MW7) exhibiting lipase, phospholipase, esterase, thioesterase, and tweenase activities. The structure of SrLip is one of a very few lipases, among the 3D-structures of the SGNH superfamily of hydrolases, structurally characterized by synchrotron diffraction data at 1.75 Å resolution (PDB: 5MAL ). Its crystal structure was determined by molecular replacement using a homology model based on the crystal structure of phospholipase A from Streptomyces albidoflavus (PDB: 4HYQ ). The structure reveals the Rossmann-like 3-layer αβα sandwich fold typical of the SGNH superfamily stabilized by three disulfide bonds. The active site shows a catalytic dyad involving Ser10 and His216 with Ser10-OγH···NεHis216, His216-NδH···O═C-Ser214, and Gly54-NH···Oγ-Ser10 hydrogen bonds essential for the catalysis; the carbonyl oxygen of the Ser214 main chain acts as a hydrogen bond acceptor ensuring the orientation of the His216 imidazole ring suitable for a proton transfer. Molecular dynamics simulations of the apoenzyme and its complex with p-nitrophenyl caprylate were used to probe the positioning of the substrate ester group within the active site and its aliphatic chain within the binding site. Quantum-mechanical calculations at the DFT level revealed the precise molecular mechanism of the SrLip catalytic activity, demonstrating that the overall hydrolysis is a two-step process with acylation as the rate-limiting step associated with the activation free energy of ΔG = 17.9 kcal mol, being in reasonable agreement with the experimental value of 14.5 kcal mol, thus providing strong support in favor of the proposed catalytic mechanism based on a dyad.