An integrated approach combining experimental, informatics and energetic methods for solid form derisking of PF-06282999.

The landscapes of observed and predicted three-dimensional crystal packing arrangements of small-molecule drug candidates can be complex. The possible appearance of a more thermodynamically stable solid form during drug development has led to the digital workflow of informatics-based risk assessments, named a Solid Form Health Check. Herein, we describe the use of a combined approach consisting of experiments, informatics together with energetic calculations in analysis of four competing polymorphs of PF-06282999, a myeloperoxidase (MPO) inhibitor with conformational flexibility and multiple plausible hydrogen bond networks.

Dynamics of collisions and uptake of alcohol molecules with hydrated nitric acid clusters.

We investigate the collisions of different alcohol molecules with hydrated nitric acid clusters using a molecular beam experiment and molecular dynamics simulations. The uptake cross sections for the molecules evaluated from the experiment are in excellent agreement with the simulations. This suggests that (i) the nontrivial assumptions implemented in the evaluation procedure of the experimental data are valid, and (ii) the simulations describe correctly the major processes in the molecule-cluster collisions.

Hydrated Formic Acid Clusters and their Interaction with Electrons.

We investigate ion formation in hydrated formic acid (FA) clusters upon collision with electrons of variable energy, focusing on electron ionization at 70 eV (EI) and low-energy (1.5-15 eV) electron attachment (EA). To uncover details about the composition of neutral clusters, we aim to elucidate the ion formation processes in FA ⋅ W clusters initiated by interaction with electrons and determine the extent of cluster fragmentation.

The molecular basis of drug selectivity for α5 subunit-containing GABA receptors.

α5 subunit-containing γ-aminobutyric acid type A (GABA) receptors represent a promising drug target for neurological and neuropsychiatric disorders. Altered expression and function contributes to neurodevelopmental disorders such as Dup15q and Angelman syndromes, developmental epilepsy and autism. Effective drug action without side effects is dependent on both α5-subtype selectivity and the strength of the positive or negative allosteric modulation (PAM or NAM).

Does HNO dissociate on gas-phase ice nanoparticles?

We investigated the dissociation of nitric acid on large water clusters (HO), ≈ 30-500, , ice nanoparticles with diameters of 1-3 nm, in a molecular beam. The (HO) clusters were doped with single HNO molecules in a pickup cell and probed by mass spectrometry after a low-energy (1.5-15 eV) electron attachment.

Ion transmission in an electrospray ionization-mass spectrometry interface using an S-lens.

We present the design and performance of an in-house built electrospray ionization-mass spectrometry (ESI-MS) interface equipped with an S-lens ion guide. The ion source was designed specifically for our ion beam experiments to investigate the chemical reactivity and deposition of the clusters and nanoparticles. It includes standard ESI-MS interface components, such as nanoelectrospray, ion transfer capillary, and the S-lens.

Herpes Simplex Virus-1 ICP27 Nuclear Export Signal Mutants Exhibit Cell Type-Dependent Deficits in Replication and ICP4 Expression.

Herpes simplex virus type-1 (HSV-1) protein ICP27 is an essential immediate early (IE) protein that promotes the expression of viral early (E) and late (L) genes via multiple mechanisms. Our understanding of this complex regulatory protein has been greatly enhanced by the characterization of HSV-1 mutants bearing engineered alterations in the ICP27 gene. However, much of this analysis has been performed in interferon-deficient Vero monkey cells.

Direct Coupling of Methane and Carbon Dioxide on Tantalum Cluster Cations.

Understanding molecular-scale reaction mechanisms is crucial for the design of modern catalysts with industrial prospect. Through joint experimental and computational studies, we investigate the direct coupling reaction of CH and CO , two abundant greenhouse gases, mediated by Ta ions to form larger oxygenated hydrocarbons. Coherent with proposed elementary steps, we expose products of CH dehydrogenation [Ta CH ] to CO in a ring electrode ion trap.

Effect of Hydration on Electron Attachment to Methanesulfonic Acid Clusters.

We report an experimental and computational study of the electron-induced chemistry of methanesulfonic acid (MSA, MeSOH) in clusters. We combine the mass spectra after the 70 eV electron ionization with the negative ion spectra after electron attachment (EA) at low electron energies of 0-15 eV of the MSA molecule, small MSA clusters, and microhydrated MSA clusters to reveal the solvation effects. The MSA/He coexpansion only generates small MSA clusters with up to four molecules, but adding water substantially hydrates the MSA clusters, resulting in clusters composed of 1-2 MSA molecules accompanied by quite a few water molecules.

CO-Activation by size-selected tantalum cluster cations (Ta): thermalization governing reaction selectivity.

The reactions of tantalum cluster cations of different sizes toward carbon dioxide are studied in an ion trap under multi-collisional conditions. For all sizes studied, consecutive reactions with several CO molecules are observed. This reveals two different pathways, namely oxide formation and the pickup of an entire molecule.

Water-Assisted Electron-Induced Chemistry of the Nanofabrication Precursor Iron Pentacarbonyl.

Focused electron beam deposition often requires the use of purification techniques to increase the metal content of the respective deposit. One of the promising methods is adding HO vapor as a reactive agent during the electron irradiation. However, various contrary effects of such addition have been reported depending on the experimental condition.

Pickup and reactions of molecules on clusters relevant for atmospheric and interstellar processes.

In this perspective, we review experiments with molecules picked up on large clusters in molecular beams with the focus on the processes in atmospheric and interstellar chemistry. First, we concentrate on the pickup itself, and we discuss the pickup cross sections. We measure the uptake of different atmospheric molecules on mixed nitric acid-water clusters and determine the accommodation coefficients relevant for aerosol formation in the Earth's atmosphere.

Temperature evolution in IR action spectroscopy experiments with sodium doped water clusters.

The combination of supersonic expansions with IR action spectroscopy techniques is the basis of many successful approaches to study cluster structure and dynamics. The effects of temperature and temperature evolution are important with regard to both the cluster synthesis and the cluster dynamics upon IR excitation. In the past the combination of the sodium doping technique with IR excitation enhanced near threshold photoionization has been successfully applied to study neutral, especially water clusters.

Carbide Dihydrides: Carbonaceous Species Identified in Ta -Mediated Methane Dehydrogenation.

The products of methane dehydrogenation by gas-phase Ta clusters are structurally characterized using infrared multiple photon dissociation (IRMPD) spectroscopy in conjunction with quantum chemical calculations. The obtained spectra of [4Ta,C,2H] reveal a dominance of vibrational bands of a H Ta C carbide dihydride structure over those indicative for a HTa CH carbyne hydride one, as is unambiguously verified by studies employing various methane isotopologues. Because methane dehydrogenation by metal cations M typically leads to the formation of either MCH carbene or HMCH carbyne hydride structures, the observation of a H MC carbide dihydride structure implies that it is imperative to consider this often-neglected class of carbonaceous intermediates in the reaction of metals with hydrocarbons.

Chemistry of NO and HNO Molecules with Gas-Phase Hydrated O and OH Ions.

The gas-phase reactions of O (H O) and OH (H O) , n=20-38, with nitrogen-containing atmospherically relevant molecules, namely NO and HNO , are studied by Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometry and theoretically with the use of DFT calculations. Hydrated O anions oxidize NO and NO to NO and NO through a strongly exothermic reaction with enthalpy of -263±47 kJ mol and -286±42 kJ mol , indicating a covalent bond formation. Comparison of the rate coefficients with collision models shows that the reactions are kinetically slow with 3.

Catalytic Non-Oxidative Coupling of Methane on TaO.

Mass-selected TaO cluster ions catalyze the transformation of methane in a gas-phase ion trap experiment via nonoxidative coupling into ethane and H, which is a prospective reaction for the generation of valuable chemicals on an industrial scale. Systematic variation of the reaction conditions and the isotopic labeling of methane by deuterium allow for an unambiguous identification of a catalytic cycle. Comparison with the proposed catalytic cycle for tantalum-doped silica catalysts reveals surprising similarities as the mechanism of the C-C coupling step, but also peculiar differences like the mechanism of the eventual formation of molecular hydrogen and ethane.

Oxidation Enhances Aerosol Nucleation: Measurement of Kinetic Pickup Probability of Organic Molecules on Hydrated Acid Clusters.

We investigate the uptake of the most prominent biogenic volatile organic compounds (VOCs)-isoprene, α-pinene, and their selected oxidation products-by hydrated acid clusters in a molecular beam experiment and by DFT calculations. Our experiments provide a unique and direct way of determination of the surface accommodation coefficient () on the proxies of ultrafine aerosol particles. Since we are able to determine unambiguously the fraction of the clusters to which the molecules stick upon collisions, our is a purely kinetic parameter disentangling the molecule pickup from its evaporation.

Radical Dimerization in a Plastic Organic Crystal Leads to Structural and Magnetic Bistability with Wide Thermal Hysteresis.

The nitroxyl radical 1-methyl-2-azaadamantane -oxyl (Me-AZADO) exhibits magnetic bistability arising from a radical/dimer interconversion. The transition from the rotationally disordered paramagnetic plastic crystal, Me-AZADO, to the ordered diamagnetic crystalline phase, (Me-AZADO), has been conclusively demonstrated by crystal structure determination from high-resolution powder diffraction data and by solid-state NMR spectroscopy. The phase change is characterized by a wide thermal hysteresis with high sensitivity to even small applied pressures.

Antiferroelectric Phase Transition in a Proton-Transfer Salt of Squaric Acid and 2,3-Dimethylpyrazine.

A proton-transfer reaction between squaric acid (Hsq) and 2,3-dimethylpyrazine (2,3-Mepyz) results in crystallization of a new organic antiferroelectric (AFE), (2,3-MepyzH)(Hsq)·HO (), which possesses a layered structure. The structure of each layer can be described as partitioned into strips lined with methyl groups of the MepyzH cations and strips featuring extensive hydrogen bonding between the Hsq anions and water molecules. Variable-temperature dielectric measurements and crystal structures determined through a combination of single-crystal X-ray and neutron diffraction reveal an AFE ordering at 104 K.

From lithium to sodium: design of heterometallic molecular precursors for the NaMO cathode materials.

Based on the well-established model structure of LiM(tbaoac), the first series of heterometallic molecular precursors NaM(tbaoac)(THF) (M = Fe, Co, and Ni) have been designed and successfully utilized for the preparation of NaMO oxide cathode materials of sodium-ion batteries.

Dissociative electron attachment to HNO and its hydrates: energy-selective electron-induced chemistry.

We probe the negative ion production upon the interaction of free electrons with gas-phase HNO3 and its mixed clusters with water. The electron-induced chemistry changes strongly with clustering, exhibiting significant electron energy dependence. For HNO3 hydrates, we identified three involved energy ranges with different behavior: low energies up to about 3.

Crystal Structure Prediction via Deep Learning.

We demonstrate the application of deep neural networks as a machine-learning tool for the analysis of a large collection of crystallographic data contained in the crystal structure repositories. Using input data in the form of multiperspective atomic fingerprints, which describe coordination topology around unique crystallographic sites, we show that the neural-network model can be trained to effectively distinguish chemical elements based on the topology of their crystallographic environment. The model also identifies structurally similar atomic sites in the entire data set of ∼50000 crystal structures, essentially uncovering trends that reflect the periodic table of elements.

Uptake of methanol on mixed HNO/HO clusters: An absolute pickup cross section.

The uptake of atmospheric oxidized organics on acid clusters is relevant for atmospheric new particle formation. We investigate the pickup of methanol (CHOH) on mixed nitric acid-water clusters (HNO)(HO) by a combination of mass spectrometry and cluster velocity measurements in a molecular beam. The mass spectra of the mixed clusters exhibit (HNO)(HO)H series with m = 0-3 and n = 0-12.

Power of Three: Incremental Increase in the Ligand Field Strength of N-Alkylated 2,2'-Biimidazoles Leads to Spin Crossover in Homoleptic Tris-Chelated Fe(II) Complexes.

Homoleptic complexes [Fe(L )]X (L = 1,1'-(α,α'- o-xylyl)-2,2'-biimidazole, L = 1,1'-(α,α'-3,4-dibromo- o-xylyl)-2,2'-biimidazole, L = 1,1'-(α,α'-2,5-dimethoxy- o-xylyl)-2,2'-biimidazole; X = BF or ClO) were synthesized by direct reactions of the Fe(II) precursor salts and bidentate ligands L, L, or L. All mononuclear complexes undergo gradual temperature-driven spin-crossover (SCO) between the high-spin (HS, S = 2) and low-spin (LS, S = 0) states. Complexes with ligands L and L synthesized in methanol exhibit complete SCO with the midpoint of the LS↔HS conversion varying from 233 to 313 K, while complexes with ligand L, crystallized from an ethanol/dichloromethane mixture, exhibit incomplete SCO with the residual HS/LS ratio of ∼1:4 for [Fe(L)](BF) and ∼1:1 for [Fe(L)](ClO).

Mass spectrometry of aerosol particle analogues in molecular beam experiments.

Nanometer-size particles such as ultrafine aerosol particles, ice nanoparticles, water nanodroplets, etc, play an important, however, not yet fully understood role in the atmospheric chemistry and physics. These species are often composed of water with admixture of other atmospherically relevant molecules. To mimic and investigate such particles in laboratory experiments, mixed water clusters with atmospherically relevant molecules can be generated in molecular beams and studied by various mass spectrometric methods.