From a humorous post to a detailed quantum-chemical study: isocyanate synthesis revisited.

Isocyanates play an essential role in modern manufacturing processes, especially in polyurethane production. There are numerous synthesis strategies for isocyanates both under industrial and laboratory conditions, which do not prevent searching for alternative highly efficient synthetic protocols. Here, we report a detailed theoretical investigation of the mechanism of sulfur dioxide-catalyzed rearrangement of phenylnitrile oxide into phenyl isocyanate, which was first reported in 1977. The DLPNO-CCSD(T) method and up-to-date DFT protocols were used to perform a highly accurate quantum-chemical study of the rearrangement mechanism. An overview of various organic and inorganic catalysts has revealed other potential catalysts, such as sulfur trioxide and selenium dioxide. Furthermore, the present study elucidated how substituents in phenylnitrile oxide influence reaction kinetics. This study was performed by a self-organized collaboration of scientists initiated by a humorous post on the VK social network.

Regularized weighted sine least-squares spectral analysis for gas electron diffraction data.

Here, we present a new approach for obtaining radial distribution functions (RDF) from the electron diffraction data using a regularized weighted sine least-squares spectral analysis. It allows for explicitly transferring the measured experimental uncertainties in the reduced molecular scattering function to the produced RDF. We provide a numerical demonstration, discuss the uncertainties and correlations in the RDFs, and suggest a regularization parameter choice criterion. The approach is also applicable for other diffraction data, e.g., for x-ray or neutron diffraction of liquid samples.

Probing the Proton-Gated ASIC Channels Using Tetraalkylammonium Ions.

The action of tetraalkylammonium ions, from tetrametylammonium (TMA) to tetrapentylammonium (TPtA), on the recombinant and native acid-sensing ion channels (ASICs) was studied using the patch-clamp approach. The responses of ASIC1a, ASIC2a, and native heteromeric ASICs were inhibited by TPtA. The peak currents through ASIC3 were unaffected, whereas the steady-state currents were significantly potentiated. This effect was characterized by an EC50 value of 1.22 ± 0.12 mM and a maximal effect of 3.2 ± 0.5. The effects of TPtA were voltage-independent but significantly decreased under conditions of strong acidification, which caused saturation of ASIC responses. Molecular modeling predicted TPtA binding in the acidic pocket of closed ASICs. Bound TPtA can prevent acidic pocket collapse through a process involving ASIC activation and desensitization. Tetraethylammonium (TEA) inhibited ASIC1a and native ASICs. The effect was independent of the activating pH but decreased with depolarization, suggesting a pore-blocking mechanism.

Executive control of language in schizophrenia patients with history of auditory verbal hallucinations: A neuropsychological and resting-state fMRI study.

BACKGROUND: As demonstrated by a plethora of studies, compromised executive functions (EF) and language are implicated in mechanisms of auditory verbal hallucinations (AVH), but the contribution of their interaction to AVH remains unclear. We hypothesized that schizophrenia patients with history of AVH (AVHh+) vs. without history of AVH (AVHh-) have a specific deficit of executive control of language and alterations in functional connectivity (FC) between the brain regions involved in EF and language, and these neuropsychological and neurophysiological traits are associated with each other. METHODS: To explore the executive control of language and its contribution to AVH, we used an integrative approach involving analysis of neuropsychological and resting-state fMRI data of 34 AVHh+, 16 AVHh-, and 40 healthy controls. We identified the neuropsychological and FC measures that differentiated between AVHh+, AVHh-, and HC, and tested the associations between them. RESULTS: AVHh+ were characterized by decreased category and phonological verbal fluency, utterance length, productivity in the planning tasks, and poorer retelling. AVHh+ had decreased FC between the left inferior frontal gyrus and the anterior cingulate cortex. Productivity in category verbal fluency was associated with the FC between these regions. CONCLUSIONS: Poor executive control of word retrieval and deficient programming of sentence and narrative related to more general deficits of planning may be the neuropsychological traits specific for AVHh+. A neurophysiological trait specific for AVHh+ may be a decreased FC between regions involved in language production and differentiation between alien- vs. self-generated speech and between language production vs. comprehension.

Light-Sensitive Open Channel Block of Ionotropic Glutamate Receptors by Quaternary Ammonium Azobenzene Derivatives.

Glutamate ionotropic receptors mediate fast excitation processes in the central nervous system of vertebrates and play an important role in synaptic plasticity, learning, and memory. Here, we describe the action of two azobenene-containing compounds, AAQ (acrylamide-azobenzene-quaternary ammonium) and QAQ (quaternary ammonium-azobenzene-quaternary ammonium), which produced rapid and fully reversible light-dependent inhibition of glutamate ionotropic receptors. The compounds demonstrated voltage-dependent inhibition with only minor voltage-independent allosteric action. Calcium-impermeable AMPA receptors had weaker sensitivity compared to NMDA and calcium-permeable AMPA receptors. We further revealed that the compounds bound to NMDA and calcium-permeable AMPA receptors in different modes. They were able to enter the wide selectivity filter of AMPA receptors, and strong negative voltages caused permeation into the cytoplasm. The narrow selectivity filter of the NMDA receptors did not allow the molecules to bypass them; therefore, QAQ and AAQ bound to the shallow channel site and prevented channel closure by a foot-in-the-door mechanism. Computer simulations employing available AMPA and NMDA receptor structures readily reproduced the experimental findings, allowing for the structure-based design of more potent and selective drugs in the future. Thus, our work creates a framework for the development of light-sensitive blockers of calcium-permeable AMPA receptors, which are desirable tools for neuroscience.

Electrodeposition and Properties of Composite Ni Coatings Modified with Multilayer Graphene Oxide.

Within the framework of this study, Ni-based composite electrochemical coatings (CECs) modified with multilayer graphene oxide (GO) processed using microwave radiation have been deposited. The process of these coatings' electrodeposition in the potentiodynamic mode has been studied. The structure of Ni-GO and Ni-GO (MW) CECs has been studied using X-ray phase analysis (XPA) and scanning electron microscopy (SEM).It has been shown that the addition of GO into a nickel deposit contributes to the formation of uniform fine-grained coatings. As a result, the microhardness of the Ni-GO (MW) CECs increases by 1.40 times compared to Ni without GO. The corrosion-electrochemical behavior of nickel CECs in 0.5 M H2SO4 solution was researched. It was established that the corrosion rate of the nickel-GO (MW) CEC in 3.5% NaCl decreases by about 1.70 times in contrast to unmodified nickel coatings. This effect is due to the absence of agglomeration of the graphene oxide in the volume of the nickel matrix and the impermeability of GO particles to the corrosive environment.

Mechanisms of dihydropyridine agonists and antagonists in view of cryo-EM structures of calcium and sodium channels.

Opposite effects of 1,4-dihydropyridine (DHP) agonists and antagonists on the L-type calcium channels are a challenging problem. Cryo-EM structures visualized DHPs between the pore-lining helices S6III and S6IV in agreement with published mutational data. However, the channel conformations in the presence of DHP agonists and antagonists are virtually the same, and the mechanisms of the ligands' action remain unclear. We docked the DHP agonist S-Bay k 8644 and antagonist R-Bay k 8644 in Cav1.1 channel models with or without π-bulges in helices S6III and S6IV. Cryo-EM structures of the DHP-bound Cav1.1 channel show a π-bulge in helix S6III but not in S6IV. The antagonist's hydrophobic group fits into the hydrophobic pocket formed by residues in S6IV. The agonists' polar NO2 group is too small to fill up the pocket. A water molecule could sterically fit into the void space, but its contacts with isoleucine in helix S6IV (motif INLF) would be unfavorable. In a model with π-bulged S6IV, this isoleucine turns away from the DHP molecule and its position is occupied by the asparagine from the same motif INLF. The asparagine provides favorable contacts for the water molecule at the agonist's NO2 group but unfavorable contacts for the antagonist's methoxy group. In our models, the DHP antagonist stabilizes entirely α-helical S6IV. In contrast, the DHP agonist stabilizes π-bulged helix S6IV whose C-terminal part turned and rearranged the activation-gate region. This would stabilize the open channel. Thus, agonists, but not antagonists, would promote channel opening by stabilizing π-bulged helix S6IV.

Possible Compensatory Role of ASICs in Glutamatergic Synapses.

Proton-gated channels of the ASIC family are widely distributed in central neurons, suggesting their role in common neurophysiological functions. They are involved in glutamatergic neurotransmission and synaptic plasticity; however, the exact function of these channels remains unclear. One problem is that acidification of the synaptic cleft due to the acidic content of synaptic vesicles has opposite effects on ionotropic glutamate receptors and ASICs. Thus, the pH values required to activate ASICs strongly inhibit AMPA receptors and almost completely inhibit NMDA receptors. This, in turn, suggests that ASICs can provide compensation for post-synaptic responses in the case of significant acidifications. We tested this hypothesis by patch-clamp recordings of rat brain neuron responses to acidifications and glutamate receptor agonists at different pH values. Hippocampal pyramidal neurons have much lower ASICs than glutamate receptor responses, whereas striatal interneurons show the opposite ratio. Cortical pyramidal neurons and hippocampal interneurons show similar amplitudes in their responses to acidification and glutamate. Consequently, the total response to glutamate agonists at different pH levels remains rather stable up to pH 6.2. Besides these pH effects, the relationship between the responses mediated by glutamate receptors and ASICs depends on the presence of Mg2+ and the membrane voltage. Together, these factors create a complex picture that provides a framework for understanding the role of ASICs in synaptic transmission and synaptic plasticity.

Describing nuclear quantum effects in vibrational properties using molecular dynamics with Wigner sampling.

In this work we discuss the generally applicable Wigner sampling and introduce a new, simplified Wigner sampling method, for computationally effective modeling of molecular properties containing nuclear quantum effects and vibrational anharmonicity. For various molecular systems test calculations of (a) vibrationally averaged rotational constants, (b) vibrational IR spectra and (c) photoelectron spectra have been performed. The performance of Wigner sampling has been assessed by comparing with experimental data and with results of other theoretical models, including harmonic and VPT2 approximations. The developed simplified Wigner sampling method shows advantages in application to large and flexible molecules.

Metadynamics simulations with Bohmian-style bias potential.

Here, we present a parametrization of the metadynamics simulations for reactions involving breaking the chemical bonds along a single collective variable coordinate. The parameterization is based on the similarity between the bias potential in metadynamics and the quantum potential in the de Broglie-Bohm formalism. We derive the method and test it on two prototypical reaction types: proton transfer and breaking of the cyclohexene cycle (reversed Diels-Alder reaction).

Inducing transient enantiomeric excess in a molecular quantum racemic mixture with microwave fields.

Chiral molecules with low enantiomer interconversion barriers racemize even at cryogenic temperatures due to quantum tunneling, forming a racemic mixture that is impossible to separate using conventional chemical methods. Here we both experimentally and theoretically demonstrate a method to create and probe a state-specific enantiomeric enrichment for such molecular systems. The coherent, non-linear, and resonant approach is based on a microwave six-wave mixing scheme and consists of five phase-controlled microwave pulses. The first three pulses induce a chiral wavepacket in a chosen rotational state, while the consecutive two pulses induce a polarization for a particular rotational transition (listen transition) with a magnitude proportional to the enantiomeric excess created. The experiments are performed with the transiently chiral molecule benzyl alcohol, where a chiral molecular response was successfully obtained. This signal demonstrates that enantiomeric excess can be induced in a quantum racemic mixture of a transiently chiral molecule using the developed microwave six-wave mixing scheme, which is an important step towards controlling non-rigid chiral molecular systems.

Analysis of residue-residue interactions in the structures of ASIC1a suggests possible gating mechanisms.

The gating mechanism of acid-sensitive ion channels (ASICs) remains unclear, despite the availability of atomic-scale structures in various functional states. The collapse of the acidic pocket and structural changes in the low-palm region are assumed to trigger activation. For the acidic pocket, protonation of some residues can minimize repulsion in the collapsed conformation. The relationship between low-palm rearrangements and gating is unknown. In this work, we performed a Monte Carlo energy optimization of known ASIC1a structures and determined the residue-residue interactions in different functional states. For rearrangements in the acidic pocket, our results are consistent with previously proposed mechanisms, although significant complexity was revealed for the residue-residue interactions. The data support the proposal of a gating mechanism in the low-palm region, in which residues E80 and E417 share a proton to activate the channel.

Derivatives of 2-aminobenzimidazole potentiate ASIC open state with slow kinetics of activation and desensitization.

The pharmacology of acid-sensitive ion channels (ASICs) is diverse, but potent and selective modulators, for instance for ASIC2a, are still lacking. In the present work we studied the effect of five 2-aminobenzimidazole derivatives on native ASICs in rat brain neurons and recombinant receptors expressed in CHO cells using the whole-cell patch clamp method. 2-aminobenzimidazole selectively potentiated ASIC3. Compound Ru-1355 strongly enhanced responses of ASIC2a and caused moderate potentiation of native ASICs and heteromeric ASIC1a/ASIC2a. The most active compound, Ru-1199, caused the strongest potentiation of ASIC2a, but also potentiated native ASICs, ASIC1a and ASIC3. The potentiating effects depended on the pH and was most pronounced with intermediate acidifications. In the presence of high concentrations of Ru-1355 and Ru-1199, the ASIC2a responses were biphasic, the initial transient currents were followed by slow component. These slow additional currents were weakly sensitive to the acid-sensitive ion channels pore blocker diminazene. We also found that sustained currents mediated by ASIC2a and ASIC3 are less sensitive to diminazene than the peak currents. Different sensitivities of peak and sustained components to the pore-blocking drug suggest that they are mediated by different open states. We propose that the main mechanism of action of 2-aminobenzimidazole derivatives is potentiation of the open state with slow kinetics of activation and desensitization.

Mechanisms of acid-sensing ion channels inhibition by nafamostat, sepimostat and diminazene.

Acid-sensing ion channels (ASICs) are blocked by many cationic compounds. Mechanisms of action, which may include pore block, modulation of activation and desensitization, need systematic analysis to allow predictable design of new potent and selective drugs. In this work, we studied the action of the serine protease inhibitors nafamostat, sepimostat, gabexate and camostat, on native ASICs in rat giant striatal interneurons and recombinant ASIC1a and ASIC2a channels, and compared it to that of well-known small molecule ASIC blocker diminazene. All these compounds have positively charged amidine and/or guanidine groups in their structure. Nafamostat, sepimostat and diminazene inhibited pH 6.5-induced currents in rat striatal interneurons at -80 mV holding voltage with IC50 values of 0.78 ± 0.12 µM, 2.4 ± 0.3 µM and 0.40 ± 0.09 µM, respectively, whereas camostat and gabexate were practically ineffective. The inhibition by nafamostat, sepimostat and diminazene was voltage-dependent evidencing binding in the channel pore. They were not trapped in the closed channels, suggesting "foot-in-the-door" mechanism of action. The inhibitory activity of nafamostat, sepimostat and diminazene was similar in experiments on native ASICs and recombinant ASIC1a channels, while all of them were drastically less active against ASIC2a channels. According to our molecular modeling, three active compounds bind in the channel pore between Glu 433 and Ala 444 in a similar way. In view of the relative safety of nafamostat for clinical use in humans, it can be considered as a potential candidate for the treatment of pathophysiological conditions linked to ASICs disfunction, including inflammatory pain and ischemic stroke.

Development of a quaternary ammonium photoswitchable antagonist of NMDA receptors.

NMDA receptors play critical roles in numerous physiological and pathological processes in CNS that requires development of modulating ligands. In particular, photoswitchable compounds that selectively target NMDA receptors would be particularly useful for analysis of receptor contributions to various processes. Recently, we identified a light-dependent anti-NMDA activity of the azobenzene-containing quaternary ammonium compounds DENAQ (diethylamine-azobenzene-quaternary ammonium) and DMNAQ (dimethylamine-azobenzene-quaternary ammonium). Here, we developed a series of light-sensitive compounds based on the DENAQ structure, and studied their action on glutamate receptors in rat brain neurons using patch-clamp method. We found that the activities of the compounds and the influence of illumination strongly depended on the structural details, as even minor structural modifications greatly altered the activity and sensitivity to illumination. The compound PyrAQ (pyrrolidine-azobenzene-quaternary ammonium) was the most active and produced fast and fully reversible inhibition of NMDA receptors. The IC50 values under ambient and monochromic light conditions were 2 and 14 µM, respectively. The anti-AMPA activity was much weaker. The action of PyrAQ did not depend on NMDA receptor activity, agonist concentration, or membrane voltage, making it a useful tool for photopharmacological studies.

Modulation of Slow Desensitization (Tachyphylaxis) of Acid-Sensing Ion Channel (ASIC)1a.

Among the proton-activated channels of the ASIC family, ASIC1a exhibits a specific tachyphylaxis phenomenon in the form of a progressive decrease in the response amplitude during a series of activations. This process is well known, but its mechanism is poorly understood. Here, we demonstrated a partial reversibility of this effect using long-term whole-cell recording of CHO cells transfected with rASIC1a cDNA. Thus, tachyphylaxis represents a slow desensitization of ASIC1a. Prolonged acidifications provided the same recovery from slow desensitization as short acidifications of the same frequency. Slow desensitization and steady-state desensitization are independent processes although the latter attenuates the development of the former. We found that drugs which facilitate ASIC1a activation (e.g., amitriptyline) cause an enhancement of slow desensitization, while inhibition of ASIC1a by 9-aminoacridine attenuates this process. Overall, for a broad variety of exposures, including increased calcium concentration, different pH conditions, and modulating drugs, we found a correlation between their effects on ASIC1a response amplitude and the development of slow desensitization. Thus, our results demonstrate that slow desensitization occurs only when ASIC1a is in the open state.

Pump-probe spectroscopy of chiral vibrational dynamics.

A planar molecule may become chiral upon excitation of an out-of-plane vibration, changing its handedness during half a vibrational period. When exciting such a vibration in an ensemble of randomly oriented molecules with an infrared laser, half of the molecules will undergo the vibration phase-shifted by π compared to the other half, and no net chiral signal is observed. This symmetry can be broken by exciting the vibrational motion with a Raman transition in the presence of a static electric field. Subsequent ionization of the vibrating molecules by an extreme ultraviolet pulse probes the time-dependent net handedness via the photoelectron circular dichroism. Our proposal for pump-probe spectroscopy of molecular chirality, based on quantum-chemical theory and discussed for the example of the carbonyl chlorofluoride molecule, is feasible with current experimental technology.

The kinetic energy of PAH dication and trication dissociation determined by recoil-frame covariance map imaging.

We investigated the dissociation of dications and trications of three polycyclic aromatic hydrocarbons (PAHs), fluorene, phenanthrene, and pyrene. PAHs are a family of molecules ubiquitous in space and involved in much of the chemistry of the interstellar medium. In our experiments, ions are formed by interaction with 30.3 nm extreme ultraviolet (XUV) photons, and their velocity map images are recorded using a PImMS2 multi-mass imaging sensor. Application of recoil-frame covariance analysis allows the total kinetic energy release (TKER) associated with multiple fragmentation channels to be determined to high precision, ranging 1.94-2.60 eV and 2.95-5.29 eV for the dications and trications, respectively. Experimental measurements are supported by Born-Oppenheimer molecular dynamics (BOMD) simulations.

Glutamate potentiates heterologously expressed homomeric acid-sensing ion channel 1a.

Acid-sensing ion channels (ASICs) participate in synaptic transmission due to the acidic content of synaptic vesicles, but their contribution to postsynaptic currents is small. This has stimulated attempts to find endogenous ASIC potentiators that could enhance ASIC-mediated currents to physiologically relevant values. Here we demonstrate that glutamate, which serves as a neurotransmitter, potentiates recombinant ASIC1a in the submillimolar concentration range. The effect of glutamate is especially interesting as ASIC's presence has been shown in glutamatergic synapses. At pH=6.5 glutamate had maximum potentiation of 87% with an EC50 value of 0.65 mM. The mechanism of potentiation is due to a shift of pH-dependent activation to less acidic values, with 0.5 mM glutamate increasing pH50 from 6.04 to 6.43. Due to this mechanism, ASIC1a in glutamatergic synapses might be intrinsically potentiated. Furthermore, this effect could compensate for the inhibition of ionotropic glutamate receptors by extracellular acidification during synaptic transmission.

P-Loop Channels: Experimental Structures, and Physics-Based and Neural Networks-Based Models.

The superfamily of P-loop channels includes potassium, sodium, and calcium channels, as well as TRP channels and ionotropic glutamate receptors. A rapidly increasing number of crystal and cryo-EM structures have revealed conserved and variable elements of the channel structures. Intriguing differences are seen in transmembrane helices of channels, which may include π-helical bulges. The bulges reorient residues in the helices and thus strongly affect their intersegment contacts and patterns of ligand-sensing residues. Comparison of the experimental structures suggests that some π-bulges are dynamic: they may appear and disappear upon channel gating and ligand binding. The AlphaFold2 models represent a recent breakthrough in the computational prediction of protein structures. We compared some crystal and cryo-EM structures of P-loop channels with respective AlphaFold2 models. Folding of the regions, which are resolved experimentally, is generally similar to that predicted in the AlphaFold2 models. The models also reproduce some subtle but significant differences between various P-loop channels. However, patterns of π-bulges do not necessarily coincide in the experimental and AlphaFold2 structures. Given the importance of dynamic π-bulges, further studies involving experimental and theoretical approaches are necessary to understand the cause of the discrepancy.