Sent packing: protein engineering generates a new crystal form of Pseudomonas aeruginosa DsbA1 with increased catalytic surface accessibility

DOE Office of Scientific and Technical Information (OSTI.GOV)

McMahon, Roisin M., E-mail: r.mcmahon1@uq.edu.au; Coinçon, Mathieu; Tay, Stephanie

The crystal structure of a P. aeruginosa DsbA1 variant is more suitable for fragment-based lead discovery efforts to identify inhibitors of this antimicrobial drug target. In the reported structures the active site of the protein can simultaneously bind multiple ligands introduced in the crystallization solution or via soaking. Pseudomonas aeruginosa is an opportunistic human pathogen for which new antimicrobial drug options are urgently sought. P. aeruginosa disulfide-bond protein A1 (PaDsbA1) plays a pivotal role in catalyzing the oxidative folding of multiple virulence proteins and as such holds great promise as a drug target. As part of a fragment-based lead discoverymore » approach to PaDsbA1 inhibitor development, the identification of a crystal form of PaDsbA1 that was more suitable for fragment-soaking experiments was sought. A previously identified crystallization condition for this protein was unsuitable, as in this crystal form of PaDsbA1 the active-site surface loops are engaged in the crystal packing, occluding access to the target site. A single residue involved in crystal-packing interactions was substituted with an amino acid commonly found at this position in closely related enzymes, and this variant was successfully used to generate a new crystal form of PaDsbA1 in which the active-site surface is more accessible for soaking experiments. The PaDsbA1 variant displays identical redox character and in vitro activity to wild-type PaDsbA1 and is structurally highly similar. Two crystal structures of the PaDsbA1 variant were determined in complex with small molecules bound to the protein active site. These small molecules (MES, glycerol and ethylene glycol) were derived from the crystallization or cryoprotectant solutions and provide a proof of principle that the reported crystal form will be amenable to co-crystallization and soaking with small molecules designed to target the protein active-site surface.« less

The Effects of Impurities on Protein Crystal Growth and Nucleation: A Preliminary Study

NASA Technical Reports Server (NTRS)

Schall, Constance A.

1998-01-01

Kubota and Mullin (1995) devised a simple model to account for the effects of impurities on crystal growth of small inorganic and organic molecules in aqueous solutions. Experimentally, the relative step velocity and crystal growth of these molecules asymptotically approach zero or non-zero values with increasing concentrations of impurities. Alternatively, the step velocity and crystal growth can linearly approach zero as the impurity concentration increases. The Kubota-Mullin model assumes that the impurity exhibits Langmuirian adsorption onto the crystal surface. Decreases in step velocities and subsequent growth rates are related to the fractional coverage (theta) of the crystal surface by adsorbed impurities; theta = Kx / (I +Kx), x = mole fraction of impurity in solution. In the presence of impurities, the relative step velocity, V/Vo, and the relative growth rate of a crystal face, G/Go, are proposed to conform to the following equations: V/Vo approx. = G/Go = 1 - (alpha)(theta). The adsorption of impurity is assumed to be rapid and in quasi-equilibrium with the crystal surface sites available. When the value of alpha, an effectiveness factor, is one the growth will asymptotically approach zero with increasing concentrations of impurity. At values less than one, growth approaches a non-zero value asymptotically. When alpha is much greater than one, there will be a linear relationship between impurity concentration and growth rates. Kubota and Mullin expect alpha to decrease with increasing supersaturation and shrinking size of a two dimensional nucleus. It is expected that impurity effects on protein crystal growth will exhibit behavior similar to that of impurities in small molecule growth. A number of proteins were added to purified chicken egg white lysozyme, the effect on crystal nucleation and growth assessed.

Validation and extraction of molecular-geometry information from small-molecule databases.

PubMed

Long, Fei; Nicholls, Robert A; Emsley, Paul; Graǽulis, Saulius; Merkys, Andrius; Vaitkus, Antanas; Murshudov, Garib N

2017-02-01

A freely available small-molecule structure database, the Crystallography Open Database (COD), is used for the extraction of molecular-geometry information on small-molecule compounds. The results are used for the generation of new ligand descriptions, which are subsequently used by macromolecular model-building and structure-refinement software. To increase the reliability of the derived data, and therefore the new ligand descriptions, the entries from this database were subjected to very strict validation. The selection criteria made sure that the crystal structures used to derive atom types, bond and angle classes are of sufficiently high quality. Any suspicious entries at a crystal or molecular level were removed from further consideration. The selection criteria included (i) the resolution of the data used for refinement (entries solved at 0.84 Å resolution or higher) and (ii) the structure-solution method (structures must be from a single-crystal experiment and all atoms of generated molecules must have full occupancies), as well as basic sanity checks such as (iii) consistency between the valences and the number of connections between atoms, (iv) acceptable bond-length deviations from the expected values and (v) detection of atomic collisions. The derived atom types and bond classes were then validated using high-order moment-based statistical techniques. The results of the statistical analyses were fed back to fine-tune the atom typing. The developed procedure was repeated four times, resulting in fine-grained atom typing, bond and angle classes. The procedure will be repeated in the future as and when new entries are deposited in the COD. The whole procedure can also be applied to any source of small-molecule structures, including the Cambridge Structural Database and the ZINC database.

Microgravity

NASA Image and Video Library

2001-01-24

The Protein Crystallization for Microgravity (DCAM) was developed at NASA's Marshall Space Flight Center. A droplet of solution with protein molecules dissolved in it is isolated in the center of a small well. In orbit, an elastomer seal is lifted so the solution can evaporate and be absorbed by a wick material. This raises the concentration of the solution, thus prompting protein molecules in the solution to form crystals. The principal investigator is Dr. Dan Carter of New Century Pharmaceuticals in Huntsville, AL.

X-ray crystal structure and small-angle X-ray scattering of sheep liver sorbitol dehydrogenase

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yennawar, Hemant; Møller, Magda; University of Copenhagen, DK-2100 Copenhagen

The X-ray crystal structure and a small-angle X-ray scattering solution structure of sheep liver sorbitol dehydrogenase have been determined. The details of the interactions that enable the tetramer scaffold to be the functional biological unit have been analyzed. The X-ray crystal structure of sheep liver sorbitol dehydrogenase (slSDH) has been determined using the crystal structure of human sorbitol dehydrogenase (hSDH) as a molecular-replacement model. slSDH crystallized in space group I222 with one monomer in the asymmetric unit. A conserved tetramer that superposes well with that seen in hSDH (despite belonging to a different space group) and obeying the 222 crystalmore » symmetry is seen in slSDH. An acetate molecule is bound in the active site, coordinating to the active-site zinc through a water molecule. Glycerol, a substrate of slSDH, also occupies the substrate-binding pocket together with the acetate designed by nature to fit large polyol substrates. The substrate-binding pocket is seen to be in close proximity to the tetramer interface, which explains the need for the structural integrity of the tetramer for enzyme activity. Small-angle X-ray scattering was also used to identify the quaternary structure of the tetramer of slSDH in solution.« less

Developments in the Implementation of Acoustic Droplet Ejection for Protein Crystallography.

PubMed

Wu, Ping; Noland, Cameron; Ultsch, Mark; Edwards, Bonnie; Harris, David; Mayer, Robert; Harris, Seth F

2016-02-01

Acoustic droplet ejection (ADE) enables crystallization experiments at the low-nanoliter scale, resulting in rapid vapor diffusion equilibration dynamics and efficient reagent usage in the empirical discovery of structure-enabling protein crystallization conditions. We extend our validation of this technology applied to the diverse physicochemical property space of aqueous crystallization reagents where dynamic fluid analysis coupled to ADE aids in accurate and precise dispensations. Addition of crystallization seed stocks, chemical additives, or small-molecule ligands effectively modulates crystallization, and we here provide examples in optimization of crystal morphology and diffraction quality by the acoustic delivery of ultra-small volumes of these cofactors. Additional applications are discussed, including set up of in situ proteolysis and alternate geometries of crystallization that leverage the small scale afforded by acoustic delivery. Finally, we describe parameters of a system of automation in which the acoustic liquid handler is integrated with a robotic arm, plate centrifuge, peeler, sealer, and stacks, which allows unattended high-throughput crystallization experimentation. © 2015 Society for Laboratory Automation and Screening.

Prediction of molecular crystal structures by a crystallographic QM/MM model with full space-group symmetry.

PubMed

Mörschel, Philipp; Schmidt, Martin U

2015-01-01

A crystallographic quantum-mechanical/molecular-mechanical model (c-QM/MM model) with full space-group symmetry has been developed for molecular crystals. The lattice energy was calculated by quantum-mechanical methods for short-range interactions and force-field methods for long-range interactions. The quantum-mechanical calculations covered the interactions within the molecule and the interactions of a reference molecule with each of the surrounding 12-15 molecules. The interactions with all other molecules were treated by force-field methods. In each optimization step the energies in the QM and MM shells were calculated separately as single-point energies; after adding both energy contributions, the crystal structure (including the lattice parameters) was optimized accordingly. The space-group symmetry was maintained throughout. Crystal structures with more than one molecule per asymmetric unit, e.g. structures with Z' = 2, hydrates and solvates, have been optimized as well. Test calculations with different quantum-mechanical methods on nine small organic molecules revealed that the density functional theory methods with dispersion correction using the B97-D functional with 6-31G* basis set in combination with the DREIDING force field reproduced the experimental crystal structures with good accuracy. Subsequently the c-QM/MM method was applied to nine compounds from the CCDC blind tests resulting in good energy rankings and excellent geometric accuracies.

Construction of nanostructures for selective lithium ion conduction using self-assembled molecular arrays in supramolecular solids

NASA Astrophysics Data System (ADS)

Moriya, Makoto

2017-12-01

In the development of innovative molecule-based materials, the identification of the structural features in supramolecular solids and the understanding of the correlation between structure and function are important factors. The author investigated the development of supramolecular solid electrolytes by constructing ion conduction paths using a supramolecular hierarchical structure in molecular crystals because the ion conduction path is an attractive key structure due to its ability to generate solid-state ion diffusivity. The obtained molecular crystals exhibited selective lithium ion diffusion via conduction paths consisting of lithium bis(trifluoromethanesulfonyl)amide (LiTFSA) and small molecules such as ether or amine compounds. In the present review, the correlation between the crystal structure and ion conductivity of the obtained molecular crystals is addressed based on the systematic structural control of the ionic conduction paths through the modification of the component molecules. The relationship between the crystal structure and ion conductivity of the molecular crystals provides a guideline for the development of solid electrolytes based on supramolecular solids exhibiting rapid and selective lithium ion conduction.

How To Design a Successful p53-MDM2/X Interaction Inhibitor: A Thorough Overview Based on Crystal Structures.

PubMed

Estrada-Ortiz, Natalia; Neochoritis, Constantinos G; Dömling, Alexander

2016-04-19

A recent therapeutic strategy in oncology is based on blocking the protein-protein interaction between the murine double minute (MDM) homologues MDM2/X and the tumor-suppressor protein p53. Inhibiting the binding between wild-type (WT) p53 and its negative regulators MDM2 and/or MDMX has become an important target in oncology to restore the antitumor activity of p53, the so-called guardian of our genome. Interestingly, based on the multiple disclosed compound classes and structural analysis of small-molecule-MDM2 adducts, the p53-MDM2 complex is perhaps the best studied and most targeted protein-protein interaction. Several classes of small molecules have been identified as potent, selective, and efficient inhibitors of the p53-MDM2/X interaction, and many co-crystal structures with the protein are available. Herein we review the properties as well as preclinical and clinical studies of these small molecules and peptides, categorized by scaffold type. A particular emphasis is made on crystallographic structures and the observed binding modes of these compounds, including conserved water molecules present. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A Method for Identifying Small-Molecule Aggregators Using Photonic Crystal Biosensor Microplates

PubMed Central

Chan, Leo L.; Lidstone, Erich A.; Finch, Kristin E.; Heeres, James T.; Hergenrother, Paul J.; Cunningham, Brian T.

2010-01-01

Small molecules identified through high-throughput screens are an essential element in pharmaceutical discovery programs. It is now recognized that a substantial fraction of small molecules exhibit aggregating behavior leading to false positive results in many screening assays, typically due to nonspecific attachment to target proteins. Therefore, the ability to efficiently identify compounds within a screening library that aggregate can streamline the screening process by eliminating unsuitable molecules from further consideration. In this work, we show that photonic crystal (PC) optical biosensor microplate technology can be used to identify and quantify small-molecule aggregation. A group of aggregators and nonaggregators were tested using the PC technology, and measurements were compared with those gathered by three alternative methods: dynamic light scattering (DLS), an α-chymotrypsin colorimetric assay, and scanning electron microscopy (SEM). The PC biosensor measurements of aggregation were confirmed by visual observation using SEM, and were in general agreement with the α-chymotrypsin assay. DLS measurements, in contrast, demonstrated inconsistent readings for many compounds that are found to form aggregates in shapes, very different from the classical spherical particles assumed in DLS modeling. As a label-free detection method, the PC biosensor aggregation assay is simple to implement and provides a quantitative direct measurement of the mass density of material adsorbed to the transducer surface, whereas the microplate-based sensor format enables compatibility with high-throughput automated liquid-handling methods used in pharmaceutical screening. PMID:20930952

Identification of the first small-molecule ligand of the neuronal receptor sortilin and structure determination of the receptor–ligand complex

DOE Office of Scientific and Technical Information (OSTI.GOV)

Andersen, Jacob Lauwring, E-mail: jla@mb.au.dk; Schrøder, Tenna Juul; Christensen, Søren

2014-02-01

The identification of the first small-molecule ligand of the neuronal receptor sortilin and structure determination of the receptor–ligand complex are reported. Sortilin is a type I membrane glycoprotein belonging to the vacuolar protein sorting 10 protein (Vps10p) family of sorting receptors and is most abundantly expressed in the central nervous system. Sortilin has emerged as a key player in the regulation of neuronal viability and has been implicated as a possible therapeutic target in a range of disorders. Here, the identification of AF40431, the first reported small-molecule ligand of sortilin, is reported. Crystals of the sortilin–AF40431 complex were obtained bymore » co-crystallization and the structure of the complex was solved to 2.7 Å resolution. AF40431 is bound in the neurotensin-binding site of sortilin, with the leucine moiety of AF40431 mimicking the binding mode of the C-terminal leucine of neurotensin and the 4-methylumbelliferone moiety of AF40431 forming π-stacking with a phenylalanine.« less

Flexible ferroelectric organic crystals

DOE PAGES

Owczarek, Magdalena; Hujsak, Karl A.; Ferris, Daniel P.; ...

2016-10-13

Flexible organic materials possessing useful electrical properties, such as ferroelectricity, are of crucial importance in the engineering of electronic devices. But, until now, only ferroelectric polymers have intrinsically met this flexibility requirement, leaving small-molecule organic ferroelectrics with room for improvement. Since both flexibility and ferroelectricity are rare properties on their own, combining them in one crystalline organic material is challenging. We report that trisubstituted haloimidazoles not only display ferroelectricity and piezoelectricity-the properties that originate from their non-centrosymmetric crystal lattice-but also lend their crystalline mechanical properties to fine-tuning in a controllable manner by disrupting the weak halogen bonds between the molecules.more » This element of control makes it possible to deliver another unique and highly desirable property, namely crystal flexibility. Moreover, the electrical properties are maintained in the flexible crystals.« less

JAK2 JH2 Fluorescence Polarization Assay and Crystal Structures for Complexes with Three Small Molecules.

PubMed

Newton, Ana S; Deiana, Luca; Puleo, David E; Cisneros, José A; Cutrona, Kara J; Schlessinger, Joseph; Jorgensen, William L

2017-06-08

A competitive fluorescence polarization (FP) assay is reported for determining binding affinities of probe molecules with the pseudokinase JAK2 JH2 allosteric site. The syntheses of the fluorescent 5 and 6 used in the assay are reported as well as K d results for 10 compounds, including JNJ7706621, NVP-BSK805, and filgotinib (GLPG0634). X-ray crystal structures of JAK2 JH2 in complex with NVP-BSK805, filgotinib, and diaminopyrimidine 8 elucidate the binding poses.

JAK2 JH2 Fluorescence Polarization Assay and Crystal Structures for Complexes with Three Small Molecules

PubMed Central

2017-01-01

A competitive fluorescence polarization (FP) assay is reported for determining binding affinities of probe molecules with the pseudokinase JAK2 JH2 allosteric site. The syntheses of the fluorescent 5 and 6 used in the assay are reported as well as Kd results for 10 compounds, including JNJ7706621, NVP-BSK805, and filgotinib (GLPG0634). X-ray crystal structures of JAK2 JH2 in complex with NVP-BSK805, filgotinib, and diaminopyrimidine 8 elucidate the binding poses. PMID:28626520

Effect of Low-Concentration Polymers on Crystal Growth in Molecular Glasses: A Controlling Role for Polymer Segmental Mobility Relative to Host Dynamics.

PubMed

Huang, Chengbin; Powell, C Travis; Sun, Ye; Cai, Ting; Yu, Lian

2017-03-02

Low-concentration polymers can strongly influence crystal growth in small-molecule glasses, a phenomenon important for improving physical stability against crystallization. We measured the velocity of crystal growth in two molecular glasses, nifedipine (NIF) and o-terphenyl (OTP), each doped with four or five different polymers. For each polymer, the concentration was fixed at 1 wt % and a wide range of molecular weights was tested. We find that a polymer additive can strongly alter the rate of crystal growth, from a 10-fold reduction to a 10-fold increase. For a given polymer, increasing molecular weight slows down crystal growth and the effect saturates around DP = 100, where DP is the degree of polymerization. For all the systems studied, the polymer effect on crystal growth rate forms a master curve in the variable (T g,polymer - T g,host )/T cryst , where T g is the glass transition temperature and T cryst is the crystallization temperature. These results support the view that a polymer's effect on crystal growth is controlled by its segmental mobility relative to the host-molecule dynamics. In the proposed model, crystal growth rejects impurities and creates local polymer-rich regions, which must be traversed by host molecules to sustain crystal growth at rates determined by polymer segmental mobility. Our results do not support the view that host-polymer hydrogen bonding plays a controlling role in crystal growth inhibition.

Investigating Small-Molecule Ligand Binding to G Protein-Coupled Receptors with Biased or Unbiased Molecular Dynamics Simulations

PubMed Central

Marino, Kristen A.; Filizola, Marta

2017-01-01

An increasing number of G protein-coupled receptor (GPCR) crystal structures provide important—albeit static—pictures of how small molecules or peptides interact with their receptors. These high-resolution structures represent a tremendous opportunity to apply molecular dynamics (MD) simulations to capture atomic-level dynamical information that is not easy to obtain experimentally. Understanding ligand binding and unbinding processes, as well as the related responses of the receptor, is crucial to the design of better drugs targeting GPCRs. Here, we discuss possible ways to study the dynamics involved in the binding of small molecules to GPCRs, using long timescale MD simulations or metadynamics-based approaches. PMID:29188572

Investigating Small-Molecule Ligand Binding to G Protein-Coupled Receptors with Biased or Unbiased Molecular Dynamics Simulations.

PubMed

Marino, Kristen A; Filizola, Marta

2018-01-01

An increasing number of G protein-coupled receptor (GPCR) crystal structures provide important-albeit static-pictures of how small molecules or peptides interact with their receptors. These high-resolution structures represent a tremendous opportunity to apply molecular dynamics (MD) simulations to capture atomic-level dynamical information that is not easy to obtain experimentally. Understanding ligand binding and unbinding processes, as well as the related responses of the receptor, is crucial to the design of better drugs targeting GPCRs. Here, we discuss possible ways to study the dynamics involved in the binding of small molecules to GPCRs, using long timescale MD simulations or metadynamics-based approaches.

Use of dye to distinguish salt and protein crystals under microcrystallization conditions

NASA Technical Reports Server (NTRS)

Cosenza, Larry (Inventor); Gester, Thomas E. (Inventor); Bray, Terry L. (Inventor); DeLucas, Lawrence J. (Inventor); Hamrick, David T. (Inventor)

2007-01-01

An improved method of screening crystal growth conditions is provided wherein molecules are crystallized from solutions containing dyes. These dyes are selectively incorporated or associated with crystals of particular character thereby rendering crystals of particular character colored and improving detection of the dyed crystals. A preferred method involves use of dyes in protein solutions overlayed by oil. Use of oil allows the use of small volumes of solution and facilitates the screening of large numbers of crystallization conditions in arrays using automated devices that dispense appropriate solutions to generate crystallization trials, overlay crystallization trials with an oil, provide appropriate conditions conducive to crystallization and enhance detection of dyed (colored) or undyed (uncolored) crystals that result.

Small-Angle Neutron Scattering Investigation of Growth Modifiers on Hydrate Crystal Surfaces

NASA Astrophysics Data System (ADS)

Sun, Thomas; Hutter, Jeffrey L.; Lin, M.; King, H. E., Jr.

1998-03-01

Hydrates are crystals consisting of small molecules enclathrated within an ice-like water cage. Suppression of their growth is important in the oil industry. The presence of small quantities of specific polymers during hydrate crystallization can induce a transition from an octahedral to planar growth habit. This symmetry breaking is surprising because of the suppression of two 111 planes relative to the other six crystallographically equivalent faces. To better understand the surface effects leading to this behavior, we have studied the surface adsorption of these growth-modifing polymers onto the hydrate crytals using SANS. The total hydrate surface area, as measured by Porod scattering, increases in the presence of the growth modifier, but, no significant increase in polymer concentration on the crystal surfaces is found. Implications for possible growth mechanisms will be discussed.

Internal vibrations of a molecule consisting of rigid segments. I - Non-interacting internal vibrations

NASA Technical Reports Server (NTRS)

He, X. M.; Craven, B. M.

1993-01-01

For molecular crystals, a procedure is proposed for interpreting experimentally determined atomic mean square anisotropic displacement parameters (ADPs) in terms of the overall molecular vibration together with internal vibrations with the assumption that the molecule consists of a set of linked rigid segments. The internal librations (molecular torsional or bending modes) are described using the variable internal coordinates of the segmented body. With this procedure, the experimental ADPs obtained from crystal structure determinations involving six small molecules (sym-trinitrobenzene, adenosine, tetra-cyanoquinodimethane, benzamide, alpha-cyanoacetic acid hydrazide and N-acetyl-L-tryptophan methylamide) have been analyzed. As a consequence, vibrational corrections to the bond lengths and angles of the molecule are calculated as well as the frequencies and force constants for each internal torsional or bending vibration.

Carbon Dots and 9AA as a Binary Matrix for the Detection of Small Molecules by Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry

NASA Astrophysics Data System (ADS)

Chen, Yongli; Gao, Dan; Bai, Hangrui; Liu, Hongxia; Lin, Shuo; Jiang, Yuyang

2016-07-01

Application of matrix-assisted laser-desorption/ionization mass spectrometry (MALDI MS) to analyze small molecules have some limitations, due to the inhomogeneous analyte/matrix co-crystallization and interference of matrix-related peaks in low m/z region. In this work, carbon dots (CDs) were for the first time applied as a binary matrix with 9-Aminoacridine (9AA) in MALDI MS for small molecules analysis. By 9AA/CDs assisted desorption/ionization (D/I) process, a wide range of small molecules, including nucleosides, amino acids, oligosaccharides, peptides, and anticancer drugs with a higher sensitivity were demonstrated in the positive ion mode. A detection limit down to 5 fmol was achieved for cytidine. 9AA/CDs matrix also exhibited excellent reproducibility compared with 9AA matrix. Moreover, by exploring the ionization mechanism of the matrix, the influence factors might be attributed to the four parts: (1) the strong UV absorption of 9AA/CDs due to their π-conjugated network; (2) the carboxyl groups modified on the CDs surface act as protonation sites for proton transfer in positive ion mode; (3) the thin layer crystal of 9AA/CDs could reach a high surface temperature more easily and lower transfer energy for LDI MS; (4) CDs could serve as a matrix additive to suppress 9AA ionization. Furthermore, this matrix was allowed for the analysis of glucose as well as nucleosides in human urine, and the level of cytidine was quantified with a linear range of 0.05-5 mM (R2 > 0.99). Therefore, the 9AA/CDs matrix was proven to be an effective MALDI matrix for the analysis of small molecules with improved sensitivity and reproducibility. This work provides an alternative solution for small molecules detection that can be further used in complex samples analysis.

Porous photonic crystal external cavity laser biosensor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Huang, Qinglan; Peh, Jessie; Hergenrother, Paul J.

2016-08-15

We report the design, fabrication, and testing of a photonic crystal (PC) biosensor structure that incorporates a porous high refractive index TiO{sub 2} dielectric film that enables immobilization of capture proteins within an enhanced surface-area volume that spatially overlaps with the regions of resonant electromagnetic fields where biomolecular binding can produce the greatest shifts in photonic crystal resonant wavelength. Despite the nanoscale porosity of the sensor structure, the PC slab exhibits narrowband and high efficiency resonant reflection, enabling the structure to serve as a wavelength-tunable element of an external cavity laser. In the context of sensing small molecule interactions withmore » much larger immobilized proteins, we demonstrate that the porous structure provides 3.7× larger biosensor signals than an equivalent nonporous structure, while the external cavity laser (ECL) detection method provides capability for sensing picometer-scale shifts in the PC resonant wavelength caused by small molecule binding. The porous ECL achieves a record high figure of merit for label-free optical biosensors.« less

Thieno[3,2-c]pyran-4-one based novel small molecules: their synthesis, crystal structure analysis and in vitro evaluation as potential anticancer agents.

PubMed

Nakhi, Ali; Adepu, Raju; Rambabu, D; Kishore, Ravada; Vanaja, G R; Kalle, Arunasree M; Pal, Manojit

2012-07-01

Novel thieno[3,2-c]pyran-4-one based small molecules were designed as potential anticancer agents. Expeditious synthesis of these compounds was carried out via a multi-step sequence consisting of few steps such as Gewald reaction, Sandmeyer type iodination, Sonogashira type coupling followed by iodocyclization and then Pd-mediated various C-C bond forming reactions. The overall strategy involved the construction of thiophene ring followed by the fused pyranone moiety and then functionalization at C-7 position of the resultant thieno[3,2-c]pyran-4-one framework. Some of the compounds synthesized showed selective growth inhibition of cancer cells in vitro among which two compounds for example, 5d and 6c showed IC(50) values in the range of 2.0-2.5 μM. The crystal structure analysis of an active compound along with hydrogen bonding patterns and molecular arrangement present within the molecule is described. Copyright © 2012 Elsevier Ltd. All rights reserved.

Concentration methods for high-resolution THz spectroscopy of nucleic-acid biomolecules and crystals

NASA Astrophysics Data System (ADS)

Brown, E. R.; Zhang, W.; Mendoza, E. A.; Kuznetsova, Y.; Brueck, S. R. J.; Rahman, M.; Norton, M. L.

2012-03-01

Biomolecules can exhibit low-lying vibrational modes in the THz region which are detectable in transmission given a strong molecular dipole moment and optical depth, and a spectrometer of adequate sensitivity. The nucleic acids are particularly interesting because of applications such as label-free gene assay, bio-agent detection, etc. However for nucleic acids, sample preparation and THz coupling are of paramount importance because of the strong absorption by liquid water and the small concentration of molecules present in physiological solutions. Concentration methods become necessary to make the THz vibrational modes detectable, either by concentrating the nucleic-acid sample itself in a small volume but large area, or by concentrating the THz radiation down to the volume of the sample. This paper summarizes one type of the first method: nanofluidic channel arrays for biological nucleic acids; and two types of the second method: (1) a circular-waveguide pinhole, and (2) a circular-waveguide, conical-horn coupling structure, both for DNA crystals. The first method has been demonstrated on a very short artificial nucleic acid [small-interfering (si) RNA (17-to-25 bp)] and a much longer, biological molecule [Lambda-phage DNA (48.5 kbp)]. The second method has been demonstrated on small (~100 micron) single crystals of DNA grown by the sitting-drop method.

Impact of Supramolecular Aggregation on the Crystallization Kinetics of Organic Compounds from the Supercooled Liquid State.

PubMed

Kalra, Arjun; Tishmack, Patrick; Lubach, Joseph W; Munson, Eric J; Taylor, Lynne S; Byrn, Stephen R; Li, Tonglei

2017-06-05

Despite numerous challenges in their theoretical description and practical implementation, amorphous drugs are of growing importance to the pharmaceutical industry. One such challenge is to gain molecular level understanding of the propensity of a molecule to form and remain as a glassy solid. In this study, a series of structurally similar diarylamine compounds was examined to elucidate the role of supramolecular aggregation on crystallization kinetics from supercooled liquid state. The structural similarity of the compounds makes it easier to isolate the molecular features that affect crystallization kinetics and glass forming ability of these compounds. To examine the role of hydrogen-bonded aggregation and motifs on crystallization kinetics, a combination of thermal and spectroscopic techniques was employed. Using variable temperature FTIR, Raman, and solid-state NMR spectroscopies, the presence of hydrogen bonding in the melt and glassy state was examined and correlated with observed phase transition behaviors. Spectroscopic results revealed that the formation of hydrogen-bonded aggregates involving carboxylic acid and pyridine nitrogen (acid-pyridine aggregates) between neighboring molecules in the melt state impedes crystallization, while the presence of carboxylic acid dimers (acid-acid dimers) in the melt favors crystallization. This study suggests that glass formation of small molecules is influenced by the type of intermolecular interactions present in the melt state and the kinetics associated with the molecules to assemble into a crystalline lattice. For the compounds that form acid-pyridine aggregates, the formation of energy degenerate chains, produced due to conformational flexibility of the molecules, presents a kinetic barrier to crystallization. The poor crystallization tendency of these aggregates stems from the highly directional hydrogen-bonding interactions needed to form the acid-pyridine chains. Conversely, for the compounds that form acid-acid dimers, the nondirectional van der Waals forces needed to construct a nucleus promote rapid assembly and crystallization.

Detecting ordered small molecule drug aggregates in live macrophages: a multi-parameter microscope image data acquisition and analysis strategy

PubMed Central

Rzeczycki, Phillip; Yoon, Gi Sang; Keswani, Rahul K.; Sud, Sudha; Stringer, Kathleen A.; Rosania, Gus R.

2017-01-01

Following prolonged administration, certain orally bioavailable but poorly soluble small molecule drugs are prone to precipitate out and form crystal-like drug inclusions (CLDIs) within the cells of living organisms. In this research, we present a quantitative multi-parameter imaging platform for measuring the fluorescence and polarization diattenuation signals of cells harboring intracellular CLDIs. To validate the imaging system, the FDA-approved drug clofazimine (CFZ) was used as a model compound. Our results demonstrated that a quantitative multi-parameter microscopy image analysis platform can be used to study drug sequestering macrophages, and to detect the formation of ordered molecular aggregates formed by poorly soluble small molecule drugs in animals. PMID:28270989

Detecting ordered small molecule drug aggregates in live macrophages: a multi-parameter microscope image data acquisition and analysis strategy.

PubMed

Rzeczycki, Phillip; Yoon, Gi Sang; Keswani, Rahul K; Sud, Sudha; Stringer, Kathleen A; Rosania, Gus R

2017-02-01

Following prolonged administration, certain orally bioavailable but poorly soluble small molecule drugs are prone to precipitate out and form crystal-like drug inclusions (CLDIs) within the cells of living organisms. In this research, we present a quantitative multi-parameter imaging platform for measuring the fluorescence and polarization diattenuation signals of cells harboring intracellular CLDIs. To validate the imaging system, the FDA-approved drug clofazimine (CFZ) was used as a model compound. Our results demonstrated that a quantitative multi-parameter microscopy image analysis platform can be used to study drug sequestering macrophages, and to detect the formation of ordered molecular aggregates formed by poorly soluble small molecule drugs in animals.

Morphological study on small molecule acceptor-based organic solar cells with efficiencies beyond 7% (Presentation Recording)

NASA Astrophysics Data System (ADS)

Ma, Wei; Yan, He

2015-10-01

Despite the essential role of fullerenes in achieving best-performance organic solar cells (OSCs), fullerene acceptors have several drawbacks including poor light absorption, high-cost production and purification. For this reason, small molecule acceptor (SMA)-based OSCs have attracted much attention due to the easy tunability of electronic and optical properties of SMA materials. In this study, polymers with temperature dependent aggregation behaviors are combined with various small molecule acceptor materials, which lead to impressive power conversion efficiencies of up to 7.3%. The morphological and aggregation properties of the polymer:small molecule blends are studied in details. It is found that the temperature-dependent aggregation behavior of polymers allows for the processing of the polymer solutions at moderately elevated temperature, and more importantly, controlled aggregation and strong crystallization of the polymer during the film cooling and drying process. This results in a well-controlled and near-ideal polymer:small molecule morphology that is controlled by polymer aggregation during warm casting and thus insensitive to the choice of small molecules. As a result, several cases of highly efficient (PCE between 6-7.3%) SMA OSCs are achieved. The second part of this presentation will describe the morphology of a new small molecule acceptor with a unique 3D structure. The relationship between molecular structure and morphology is revealed.

Ultratight crystal packing of a 10 kDa protein

DOE Office of Scientific and Technical Information (OSTI.GOV)

Trillo-Muyo, Sergio; Jasilionis, Andrius; Domagalski, Marcin J.

2013-03-01

The crystal structure of the C-terminal domain of a putative U32 peptidase from G. thermoleovorans is reported; it is one of the most tightly packed protein structures reported to date. While small organic molecules generally crystallize forming tightly packed lattices with little solvent content, proteins form air-sensitive high-solvent-content crystals. Here, the crystallization and full structure analysis of a novel recombinant 10 kDa protein corresponding to the C-terminal domain of a putative U32 peptidase are reported. The orthorhombic crystal contained only 24.5% solvent and is therefore among the most tightly packed protein lattices ever reported.

Beyond small molecule SAR – using the dopamine D3 receptor crystal structure to guide drug design

PubMed Central

Keck, Thomas M.; Burzynski, Caitlin; Shi, Lei; Newman, Amy Hauck

2016-01-01

The dopamine D3 receptor is a target of pharmacotherapeutic interest in a variety of neurological disorders including schizophrenia, restless leg syndrome, and drug addiction. The high protein sequence homology between the D3 and D2 receptors has posed a challenge to developing D3 receptor-selective ligands whose behavioral actions can be attributed to D3 receptor engagement, in vivo. However, through primarily small molecule structure-activity relationship (SAR) studies, a variety of chemical scaffolds have been discovered over the past two decades that have resulted in several D3 receptor-selective ligands with high affinity and in vivo activity. Nevertheless, viable clinical candidates remain limited. The recent determination of the high-resolution crystal structure of the D3 receptor has invigorated structure-based drug design, providing refinements to the molecular dynamic models and testable predictions about receptor-ligand interactions. This review will highlight recent preclinical and clinical studies demonstrating potential utility of D3 receptor-selective ligands in the treatment of addiction. In addition, new structure-based rational drug design strategies for D3 receptor-selective ligands that complement traditional small molecule SAR to improve the selectivity and directed efficacy profiles are examined. PMID:24484980

An ABA-mimicking ligand that reduces water loss and promotes drought resistance in plants

PubMed Central

Cao, Minjie; Liu, Xue; Zhang, Yan; Xue, Xiaoqian; Zhou, X Edward; Melcher, Karsten; Gao, Pan; Wang, Fuxing; Zeng, Liang; Zhao, Yang; Zhao, Yang; Deng, Pan; Zhong, Dafang; Zhu, Jian-Kang; Xu, H Eric; Xu, Yong

2013-01-01

Abscisic acid (ABA) is the most important hormone for plants to resist drought and other abiotic stresses. ABA binds directly to the PYR/PYL family of ABA receptors, resulting in inhibition of type 2C phosphatases (PP2C) and activation of downstream ABA signaling. It is envisioned that intervention of ABA signaling by small molecules could help plants to overcome abiotic stresses such as drought, cold and soil salinity. However, chemical instability and rapid catabolism by plant enzymes limit the practical application of ABA itself. Here we report the identification of a small molecule ABA mimic (AM1) that acts as a potent activator of multiple members of the family of ABA receptors. In Arabidopsis, AM1 activates a gene network that is highly similar to that induced by ABA. Treatments with AM1 inhibit seed germination, prevent leaf water loss, and promote drought resistance. We solved the crystal structure of AM1 in complex with the PYL2 ABA receptor and the HAB1 PP2C, which revealed that AM1 mediates a gate-latch-lock interacting network, a structural feature that is conserved in the ABA-bound receptor/PP2C complex. Together, these results demonstrate that a single small molecule ABA mimic can activate multiple ABA receptors and protect plants from water loss and drought stress. Moreover, the AM1 complex crystal structure provides a structural basis for designing the next generation of ABA-mimicking small molecules. PMID:23835477

Report on the sixth blind test of organic crystal structure prediction methods

PubMed Central

Reilly, Anthony M.; Cooper, Richard I.; Adjiman, Claire S.; Bhattacharya, Saswata; Boese, A. Daniel; Brandenburg, Jan Gerit; Bygrave, Peter J.; Bylsma, Rita; Campbell, Josh E.; Car, Roberto; Case, David H.; Chadha, Renu; Cole, Jason C.; Cosburn, Katherine; Cuppen, Herma M.; Curtis, Farren; Day, Graeme M.; DiStasio Jr, Robert A.; Dzyabchenko, Alexander; van Eijck, Bouke P.; Elking, Dennis M.; van den Ende, Joost A.; Facelli, Julio C.; Ferraro, Marta B.; Fusti-Molnar, Laszlo; Gatsiou, Christina-Anna; Gee, Thomas S.; de Gelder, René; Ghiringhelli, Luca M.; Goto, Hitoshi; Grimme, Stefan; Guo, Rui; Hofmann, Detlef W. M.; Hoja, Johannes; Hylton, Rebecca K.; Iuzzolino, Luca; Jankiewicz, Wojciech; de Jong, Daniël T.; Kendrick, John; de Klerk, Niek J. J.; Ko, Hsin-Yu; Kuleshova, Liudmila N.; Li, Xiayue; Lohani, Sanjaya; Leusen, Frank J. J.; Lund, Albert M.; Lv, Jian; Ma, Yanming; Marom, Noa; Masunov, Artëm E.; McCabe, Patrick; McMahon, David P.; Meekes, Hugo; Metz, Michael P.; Misquitta, Alston J.; Mohamed, Sharmarke; Monserrat, Bartomeu; Needs, Richard J.; Neumann, Marcus A.; Nyman, Jonas; Obata, Shigeaki; Oberhofer, Harald; Oganov, Artem R.; Orendt, Anita M.; Pagola, Gabriel I.; Pantelides, Constantinos C.; Pickard, Chris J.; Podeszwa, Rafal; Price, Louise S.; Price, Sarah L.; Pulido, Angeles; Read, Murray G.; Reuter, Karsten; Schneider, Elia; Schober, Christoph; Shields, Gregory P.; Singh, Pawanpreet; Sugden, Isaac J.; Szalewicz, Krzysztof; Taylor, Christopher R.; Tkatchenko, Alexandre; Tuckerman, Mark E.; Vacarro, Francesca; Vasileiadis, Manolis; Vazquez-Mayagoitia, Alvaro; Vogt, Leslie; Wang, Yanchao; Watson, Rona E.; de Wijs, Gilles A.; Yang, Jack; Zhu, Qiang; Groom, Colin R.

2016-01-01

The sixth blind test of organic crystal structure prediction (CSP) methods has been held, with five target systems: a small nearly rigid molecule, a polymorphic former drug candidate, a chloride salt hydrate, a co-crystal and a bulky flexible molecule. This blind test has seen substantial growth in the number of participants, with the broad range of prediction methods giving a unique insight into the state of the art in the field. Significant progress has been seen in treating flexible molecules, usage of hierarchical approaches to ranking structures, the application of density-functional approximations, and the establishment of new workflows and ‘best practices’ for performing CSP calculations. All of the targets, apart from a single potentially disordered Z′ = 2 polymorph of the drug candidate, were predicted by at least one submission. Despite many remaining challenges, it is clear that CSP methods are becoming more applicable to a wider range of real systems, including salts, hydrates and larger flexible molecules. The results also highlight the potential for CSP calculations to complement and augment experimental studies of organic solid forms. PMID:27484368

Role of Polymorphism and Thin-Film Morphology in Organic Semiconductors Processed by Solution Shearing

PubMed Central

2018-01-01

Organic semiconductors (OSCs) are promising materials for cost-effective production of electronic devices because they can be processed from solution employing high-throughput techniques. However, small-molecule OSCs are prone to structural modifications because of the presence of weak van der Waals intermolecular interactions. Hence, controlling the crystallization in these materials is pivotal to achieve high device reproducibility. In this perspective article, we focus on controlling polymorphism and morphology in small-molecule organic semiconducting thin films deposited by solution-shearing techniques compatible with roll-to-roll systems. Special attention is paid to the influence that the different experimental deposition parameters can have on thin films. Further, the main characterization techniques for thin-film structures are reviewed, highlighting the in situ characterization tools that can provide crucial insights into the crystallization mechanisms. PMID:29503976

Solutal Convection Around Growing Protein Crystal and Diffusional Purification in Space

NASA Technical Reports Server (NTRS)

Lee, Chun P.; Chernov, Alexander A.

2004-01-01

At least some protein crystals were found to preferentially trap microheterogeneous impurities. The latter are, for example, dimmer molecules of the crystallizing proteines (e.g. ferritin, lysozyme), or the regular molecules on which surfaces small molecules or ions are adsorbed (e.g. acetilated lysozyme) and modi@ molecular charge. Impurities may induce lattice defects and deteriorate structural resolution. Distribution of impurities between mother solution and gorwing crystal is defined by two interrelated distribution coefficients: kappa = rho(sup c, sub 2) and K = (rho(sup c, sub 2)/rho(sup c, sub 1)/rho(sub 2)/rho(sub 1). Here, rho(sub 2), rho(sub 1) and rho(sup c, sub 2) are densities of impurity (2) and regular protein (1) in solution at the growing interface and within the crystal ("c"). For the microheterogeneous impurities studied, K approx. = 2 - 4, so that kappa approx. - 10(exp 2) - 10(exp 3), since K = kappa (rho(sub 1)/rho(sup c, sub 1) and protein solubility ratio rho(sub 1)/rho(sub=p c, sub 2) much less than 1. Therefore, a crystal growing in absence of convection purifies mother solution around itself, grows cleaner and, probably, more perfect. If convection is present, the solution flow permanently brings new impurities to the crystal. This work theoretically addressed two subjects: 1) onset of convection, 2) distribution of impurities.

Observable Protein Crystal Growth Apparatus

NASA Technical Reports Server (NTRS)

2001-01-01

This diagram shows a cross sectrion of the fluid volume of an individual cell in the Observable Protein Crystal Growth Apparatus (OPCGA) to be operated aboard the International Space Station (ISS). The principal investigator is Dr. Alex McPherson of the University of California, Irvine. Each individual cell comprises two sample chambers with a rotating center section that isolates the two from each other until the start of the experiment and after it is completed. The cells are made from optical-quality quartz glass to allow photography and interferometric observations. Each cell has a small light-emitting diode and lens to back-light the solution. In protein crystal growth experiments, a precipitating agent such as a salt solution is used to absorb and hold water but repel the protein molecules. This increases the concentration of protein until the molecules nucleate to form crystals. This cell is one of 96 that make up the experiment module portion of the OPCGA.

One-dimensional self-confinement promotes polymorph selection in large-area organic semiconductor thin films.

PubMed

Giri, Gaurav; Li, Ruipeng; Smilgies, Detlef-M; Li, Er Qiang; Diao, Ying; Lenn, Kristina M; Chiu, Melanie; Lin, Debora W; Allen, Ranulfo; Reinspach, Julia; Mannsfeld, Stefan C B; Thoroddsen, Sigurdur T; Clancy, Paulette; Bao, Zhenan; Amassian, Aram

2014-04-16

A crystal's structure has significant impact on its resulting biological, physical, optical and electronic properties. In organic electronics, 6,13(bis-triisopropylsilylethynyl)pentacene (TIPS-pentacene), a small-molecule organic semiconductor, adopts metastable polymorphs possessing significantly faster charge transport than the equilibrium crystal when deposited using the solution-shearing method. Here, we use a combination of high-speed polarized optical microscopy, in situ microbeam grazing incidence wide-angle X-ray-scattering and molecular simulations to understand the mechanism behind formation of metastable TIPS-pentacene polymorphs. We observe that thin-film crystallization occurs first at the air-solution interface, and nanoscale vertical spatial confinement of the solution results in formation of metastable polymorphs, a one-dimensional and large-area analogy to crystallization of polymorphs in nanoporous matrices. We demonstrate that metastable polymorphism can be tuned with unprecedented control and produced over large areas by either varying physical confinement conditions or by tuning energetic conditions during crystallization through use of solvent molecules of various sizes.

Definition study for temperature control in advanced protein crystal growth

NASA Technical Reports Server (NTRS)

Nyce, Thomas A.; Rosenberger, Franz; Sowers, Jennifer W.; Monaco, Lisa A.

1990-01-01

Some of the technical requirements for an expedient application of temperature control to advanced protein crystal growth activities are defined. Lysozome was used to study the effects of temperature ramping and temperature gradients for nucleation/dissolution and consecutive growth of sizable crystals and, to determine a prototype temperature program. The solubility study was conducted using equine serum albumin (ESA) which is an extremely stable, clinically important protein due to its capability to bind and transport many different small ions and molecules.

Likelihood of atom-atom contacts in crystal structures of halogenated organic compounds.

PubMed

Jelsch, Christian; Soudani, Sarra; Ben Nasr, Cherif

2015-05-01

The likelihood of occurrence of intermolecular contacts in crystals of halogenated organic compounds has been analysed statistically using tools based on the Hirshfeld surface. Several families of small halogenated molecules (containing organic F, Cl, Br or I atoms) were analysed, based on chemical composition and aromatic or aliphatic character. The behaviour of crystal contacts was also probed for molecules containing O or N. So-called halogen bonding (a halogen making short interactions with O or N, or a π interaction with C) is generally disfavoured, except when H is scarce on the molecular surface. Similarly, halogen⋯halogen contacts are more rare than expected, except for molecules that are poor in H. In general, the H atom is found to be the preferred partner of organic halogen atoms in crystal structures. On the other hand, C⋯C interactions in parallel π-stacking have a high propensity to occur in halogenated aromatic molecules. The behaviour of the four different halogen species (F, Cl, Br, I) is compared in several chemical composition contexts. The analysis tool can be refined by distinguishing several types for a given chemical species, such as H atoms bound to O or C. Such distinction shows, for instance, that C-H⋯Cl and O-H⋯O are the preferred interactions in compounds containing both O and Cl.

Solvent additive effects on small molecule crystallization in bulk heterojunction solar cells probed during spin casting.

PubMed

Perez, Louis A; Chou, Kang Wei; Love, John A; van der Poll, Thomas S; Smilgies, Detlef-M; Nguyen, Thuc-Quyen; Kramer, Edward J; Amassian, Aram; Bazan, Guillermo C

2013-11-26

Solvent additive processing can lead to drastic improvements in the power conversion efficiency (PCE) in solution processable small molecule (SPSM) bulk heterojunction solar cells. In situ grazing incidence wide-angle X-ray scattering is used to investigate the kinetics of crystallite formation during and shortly after spin casting. The additive is shown to have a complex effect on structural evolution invoking polymorphism and enhanced crystalline quality of the donor SPSM. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Preventing Small Molecule Nucleation and Crystallization by Sequestering in a Micelle Corona

NASA Astrophysics Data System (ADS)

Li, Ziang; Johnson, Lindsay; Ricarte, Ralm; Yao, Letitia; Hillmyer, Marc; Bates, Frank; Lodge, Timothy

We exploited a blend of hydroxypropyl methylcellulose acetate succinate and poly(N-isopropylacrylamide) (PNIPAm) to improve the solubility and dissolution of a rapidly crystallizing model drug molecule phenytoin and observed synergistic effect in vitro at constant drug loading by varying the blending ratio. Dynamic and static light scattering experiments showed that PNIPAm self-assembled into micelles in aqueous solution. We believe that adding these PNIPAm micelles inhibited both nucleation and crystal growth of phenytoin based on the polarized light micrographs taken from the dissolution media. The drug-polymer intermolecular interaction was revealed by nuclear Overhauser effect spectroscopy and further quantified by diffusion ordered spectroscopy. We found that the phenytoin molecules were sequestered in aqueous solution by partitioning into the corona of the micelle. The blend strategy through the use of self-assembled micelles showcased in this study offers a new platform for designing advanced excipients for oral drug delivery. This study was funded by The Dow Chemical Company through Agreement 224249AT with the University of Minnesota.

The detection of conformational disorder by thermal analysis

NASA Astrophysics Data System (ADS)

Wunderlich, B.

Conformational disorder in crystals is found in many molecules that possess a plurality of conformational isomers. Typical examples are linear macromolecules such as polyethylene, polytetrafluoroethylene and trans-1,4-polybutadiene; and small molecules such as paraffins, cycloparaffins, soaps, lipids and many liquid-crystal forming molecules. Conformational motion is often coupled with the cooperative creation of disorder. In this case a heat and entropy of transition is observed by thermal analysis. Levels of transition entropies can be estimated, assuming most of the disorder can be traced to conformational isomerism. In case there is conformational disorder frozen-in at low temperature, thermal analysis can be used to find the glass transition of a condis crystal. An Advanced Thermal Analysis System has been developed, and will be described that permits a detailed interpretation of the thermal analysis traces. It rests with the establishment of high quality heat capacity for the rigid solid state (vibration only) and the mobile liquid state (vibrations and large amplitude cooperative motion).

The detection of conformational disorder by thermal analysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wunderlich, B.

1988-01-01

Conformational disorder in crystals is found in many molecules that possess a plurality of conformational isomers. Typical examples are linear macromolecules such as polyethylene, polytetrafluoroethylene and trans-1,4-polybutadiene; and small molecules such as paraffins, cycloparaffins, soaps, lipids and many liquid-crystal forming molecules. Conformational motion is often coupled with the cooperative creation of disorder. In this case a heat and entropy of transition is observed by thermal analysis. Levels of transition entropies can be estimated, assuming most of the disorder can be traced to conformational isomerism. In case there is conformational disorder frozen-in at low temperature, thermal analysis can be used tomore » find the glass transition of a condis crystal. An Advanced Thermal Analysis System has been developed, and will be described that permits a detailed interpretation of the thermal analysis traces. It rests with the establishment of high quality heat capacity for the rigid solid state (vibration only) and the mobile liquid state (vibrations and large amplitude cooperative motion). 36 refs., 3 figs.« less

Role of intermolecular charge delocalization and its dimensionality in efficient band-like electron transport in crystalline 2,5-difluoro-7,7,8,8-tetracyanoquinodimethane (F2-TCNQ).

PubMed

Sosorev, Andrey Yu

2017-09-27

Theoretical understanding of charge transport in organic semiconductors is exclusively important for organic electronics, but still remains a subject of debate. The recently discovered record-high band-like electron mobility in single crystals of 2,5-difluoro-7,7,8,8-tetracyanoquinodimethane (F 2 -TCNQ) is challenging from the theoretical viewpoint. First, the very small size of the F 2 -TCNQ molecule implies high reorganization energy that seems incompatible with efficient charge transport. Second, it is not clear why the crystals of a similar compound, 7,7,8,8-tetracyanoquinodimethane (TCNQ), show an inefficient hopping electron transport mechanism. To address these issues, we apply DFT and QM/MM calculations to the F n -TCNQ (n = 0,2,4) crystal series. We show that multidimensional intermolecular charge delocalization is of key importance for efficient charge transport in materials consisting of small-sized molecules, and commonly used guidelines for the search for high-mobility organic semiconductors are to be corrected.

Screened dipolar interactions in some molecular crystals

NASA Astrophysics Data System (ADS)

Munn, R. W.; Hurst, M.

1990-10-01

Screened dipole energies and dipole electric fields are calculated for the crystals of HCN, meta- and para-nitroaniline, the nonlinear optical compounds POM, MAP and DAN, meta-dinitrobenzene, and acetanilide. Only para-nitroaniline is centrosymmetric, but all the crystals have significant negative dipole energies (of the order of -20 kJ mol -1) except for POM and metadinitrobenzene, where they are positive but small in magnitude. Local dipole fields are of the order of 10 GV m -1. The results assume that surface charge annuls any macroscopic dipole field. It is speculated that the observed preponderance of centrosymmetric crystals of polar molecules may reflect a favourable dipole energy in the initial crystal nucleus rather than the macroscopic crystal.

Hydrogen-bonded diketopyrrolopyrrole (DPP) pigments as organic semiconductors

DOE PAGES

Glowacki, Eric Daniel; Coskun, Halime; Blood-Forsythe, Martin A.; ...

2014-10-13

Diketopyrrolopyrroles (DPPs) have recently gained attention as building-blocks for organic semiconducting polymers and small molecules, however the semiconducting properties of their hydrogen-bonded (H-bonded) pigment forms have not been explored. Herein we report on the performance of three archetypical H-bonded DPP pigments, which show ambipolar carrier mobilities in the range 0.01–0.06 cm 2/V s in organic field-effect transistors. Their semiconducting properties are correlated with crystal structure, where an H-bonded crystal lattice supports close and relatively cofacial π–π stacking. To better understand transport in these systems, density functional theory calculations were carried out, indicating theoretical maximum ambipolar mobility values of ~0.3 cmmore » 2/V s. Furthermore, based on these experimental and theoretical results, H-bonded DPPs represent a viable alternative to more established DPP-containing polymers and small molecules where H-bonding is blocked by N-alkylation.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stauber, Mark; Jakoncic, Jean; Berger, Jacob

Chiral control of crystallization has ample precedent in the small-molecule world, but relatively little is known about the role of chirality in protein crystallization. In this study, lysozyme was crystallized in the presence of the chiral additive 2-methyl-2,4-pentanediol (MPD) separately using the R and S enantiomers as well as with a racemic RS mixture. Crystals grown with ( R)-MPD had the most order and produced the highest resolution protein structures. This result is consistent with the observation that in the crystals grown with ( R)-MPD and ( RS)-MPD the crystal contacts are made by ( R)-MPD, demonstrating that there ismore » preferential interaction between lysozyme and this enantiomer. These findings suggest that chiral interactions are important in protein crystallization.« less

Crystal structure of a c-kit promoter quadruplex reveals the structural role of metal ions and water molecules in maintaining loop conformation.

PubMed

Wei, Dengguo; Parkinson, Gary N; Reszka, Anthony P; Neidle, Stephen

2012-05-01

We report here the 1.62 Å crystal structure of an intramolecular quadruplex DNA formed from a sequence in the promoter region of the c-kit gene. This is the first reported crystal structure of a promoter quadruplex and the first observation of localized magnesium ions in a quadruplex structure. The structure reveals that potassium and magnesium ions have an unexpected yet significant structural role in stabilizing particular quadruplex loops and grooves that is distinct from but in addition to the role of potassium ions in the ion channel at the centre of all quadruplex structures. The analysis also shows how ions cluster together with structured water molecules to stabilize the quadruplex arrangement. This particular quadruplex has been previously studied by NMR methods, and the present X-ray structure is in accord with the earlier topology assignment. However, as well as the observations of potassium and magnesium ions, the crystal structure has revealed a highly significant difference in the dimensions of the large cleft in the structure, which is a plausible target for small molecules. This difference can be understood by the stabilizing role of structured water networks.

Small molecule inhibitors of mesotrypsin from a structure-based docking screen

DOE PAGES

Kayode, Olumide; Huang, Zunnan; Soares, Alexei S.; ...

2017-05-02

PRSS3/mesotrypsin is an atypical isoform of trypsin, the upregulation of which has been implicated in promoting tumor progression. To date there are no mesotrypsin-selective pharmacological inhibitors which could serve as tools for deciphering the pathological role of this enzyme, and could potentially form the basis for novel therapeutic strategies targeting mesotrypsin. A virtual screen of the Natural Product Database (NPD) and Food and Drug Administration (FDA) approved Drug Database was conducted by high-throughput molecular docking utilizing crystal structures of mesotrypsin. Twelve high-scoring compounds were selected for testing based on lowest free energy docking scores, interaction with key mesotrypsin active sitemore » residues, and commercial availability. Diminazene (C1D22956468), along with two similar compounds presenting the bis-benzamidine substructure, was validated as a competitive inhibitor of mesotrypsin and other human trypsin isoforms. Diminazene is the most potent small molecule inhibitor of mesotrypsin reported to date with an inhibitory constant (K i) of 3.6±0.3 pM. Diminazene was subsequently co-crystalized with mesotrypsin and the crystal structure was solved and refined to 1.25 Å resolution. This high resolution crystal structure can now offer a foundation for structure-guided efforts to develop novel and potentially more selective mesotrypsin inhibitors based on similar molecular substructures.« less

Small molecule inhibitors of mesotrypsin from a structure-based docking screen

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kayode, Olumide; Huang, Zunnan; Soares, Alexei S.

PRSS3/mesotrypsin is an atypical isoform of trypsin, the upregulation of which has been implicated in promoting tumor progression. To date there are no mesotrypsin-selective pharmacological inhibitors which could serve as tools for deciphering the pathological role of this enzyme, and could potentially form the basis for novel therapeutic strategies targeting mesotrypsin. A virtual screen of the Natural Product Database (NPD) and Food and Drug Administration (FDA) approved Drug Database was conducted by high-throughput molecular docking utilizing crystal structures of mesotrypsin. Twelve high-scoring compounds were selected for testing based on lowest free energy docking scores, interaction with key mesotrypsin active sitemore » residues, and commercial availability. Diminazene (C1D22956468), along with two similar compounds presenting the bis-benzamidine substructure, was validated as a competitive inhibitor of mesotrypsin and other human trypsin isoforms. Diminazene is the most potent small molecule inhibitor of mesotrypsin reported to date with an inhibitory constant (K i) of 3.6±0.3 pM. Diminazene was subsequently co-crystalized with mesotrypsin and the crystal structure was solved and refined to 1.25 Å resolution. This high resolution crystal structure can now offer a foundation for structure-guided efforts to develop novel and potentially more selective mesotrypsin inhibitors based on similar molecular substructures.« less

Protein crystal growth in low gravity

NASA Technical Reports Server (NTRS)

Feigelson, Robert S.

1990-01-01

The effect of low gravity on the growth of protein crystals and those parameters which will affect growth and crystal quality was studied. The proper design of the flight hardware and experimental protocols are highly dependent on understanding the factors which influence the nucleation and growth of crystals of biological macromolecules. Thus, those factors are investigated and the body of knowledge which has been built up for small molecule crystallization. These data also provide a basis of comparison for the results obtained from low-g experiments. The flows around growing crystals are detailed. The preliminary study of the growth of isocitrate lyase, the crystal morphologies found and the preliminary x ray results are discussed. The design of two apparatus for protein crystal growth by temperature control are presented along with preliminary results.

Crystallization of lysozyme with ( R)-, ( S)- and ( RS)-2-methyl-2,4-pentanediol

DOE PAGES

Stauber, Mark; Jakoncic, Jean; Berger, Jacob; ...

2015-03-01

Chiral control of crystallization has ample precedent in the small-molecule world, but relatively little is known about the role of chirality in protein crystallization. In this study, lysozyme was crystallized in the presence of the chiral additive 2-methyl-2,4-pentanediol (MPD) separately using the R and S enantiomers as well as with a racemic RS mixture. Crystals grown with ( R)-MPD had the most order and produced the highest resolution protein structures. This result is consistent with the observation that in the crystals grown with ( R)-MPD and ( RS)-MPD the crystal contacts are made by ( R)-MPD, demonstrating that there ismore » preferential interaction between lysozyme and this enantiomer. These findings suggest that chiral interactions are important in protein crystallization.« less

The active site of hen egg-white lysozyme: flexibility and chemical bonding

DOE Office of Scientific and Technical Information (OSTI.GOV)

Held, Jeanette, E-mail: jeanette.netzel@uni-bayreuth.de; Smaalen, Sander van

Chemical bonding at the active site of lysozyme is analyzed on the basis of a multipole model employing transferable multipole parameters from a database. Large B factors at low temperatures reflect frozen-in disorder, but therefore prevent a meaningful free refinement of multipole parameters. Chemical bonding at the active site of hen egg-white lysozyme (HEWL) is analyzed on the basis of Bader’s quantum theory of atoms in molecules [QTAIM; Bader (1994 ▶), Atoms in Molecules: A Quantum Theory. Oxford University Press] applied to electron-density maps derived from a multipole model. The observation is made that the atomic displacement parameters (ADPs) ofmore » HEWL at a temperature of 100 K are larger than ADPs in crystals of small biological molecules at 298 K. This feature shows that the ADPs in the cold crystals of HEWL reflect frozen-in disorder rather than thermal vibrations of the atoms. Directly generalizing the results of multipole studies on small-molecule crystals, the important consequence for electron-density analysis of protein crystals is that multipole parameters cannot be independently varied in a meaningful way in structure refinements. Instead, a multipole model for HEWL has been developed by refinement of atomic coordinates and ADPs against the X-ray diffraction data of Wang and coworkers [Wang et al. (2007), Acta Cryst. D63, 1254–1268], while multipole parameters were fixed to the values for transferable multipole parameters from the ELMAM2 database [Domagala et al. (2012), Acta Cryst. A68, 337–351] . Static and dynamic electron densities based on this multipole model are presented. Analysis of their topological properties according to the QTAIM shows that the covalent bonds possess similar properties to the covalent bonds of small molecules. Hydrogen bonds of intermediate strength are identified for the Glu35 and Asp52 residues, which are considered to be essential parts of the active site of HEWL. Furthermore, a series of weak C—H⋯O hydrogen bonds are identified by means of the existence of bond critical points (BCPs) in the multipole electron density. It is proposed that these weak interactions might be important for defining the tertiary structure and activity of HEWL. The deprotonated state of Glu35 prevents a distinction between the Phillips and Koshland mechanisms.« less

Chiral Symmetry Breaking in Crystal Growth: Is Hydrodynamic Convection Relevant?

NASA Technical Reports Server (NTRS)

Martin, B.; Tharrington, A.; Wu, Xiao-Lun

1996-01-01

The effects of mechanical stirring on nucleation and chiral symmetry breaking have been investigated for a simple inorganic molecule, sodium chlorate (NaClO3). In contrast to earlier findings, our experiment suggests that the symmetry breaking may have little to do with hydrodynamic convection. Rather the effect can be reasonably accounted for by mechanical damage to incipient crystals. The catastrophic events, creating numerous small 'secondary' crystals, produce statistical domination of one chiral species over the other. Our conclusion is supported by a number of observations using different mixing mechanisms.

Crystal Structure of Mycobacterium tuberculosis H37Rv AldR (Rv2779c), a Regulator of the ald Gene: DNA BINDING AND IDENTIFICATION OF SMALL MOLECULE INHIBITORS.

PubMed

Dey, Abhishek; Shree, Sonal; Pandey, Sarvesh Kumar; Tripathi, Rama Pati; Ramachandran, Ravishankar

2016-06-03

Here we report the crystal structure of M. tuberculosis AldR (Rv2779c) showing that the N-terminal DNA-binding domains are swapped, forming a dimer, and four dimers are assembled into an octamer through crystal symmetry. The C-terminal domain is involved in oligomeric interactions that stabilize the oligomer, and it contains the effector-binding sites. The latter sites are 30-60% larger compared with homologs like MtbFFRP (Rv3291c) and can consequently accommodate larger molecules. MtbAldR binds to the region upstream to the ald gene that is highly up-regulated in nutrient-starved tuberculosis models and codes for l-alanine dehydrogenase (MtbAld; Rv2780). Further, the MtbAldR-DNA complex is inhibited upon binding of Ala, Tyr, Trp and Asp to the protein. Studies involving a ligand-binding site G131T mutant show that the mutant forms a DNA complex that cannot be inhibited by adding the amino acids. Comparative studies suggest that binding of the amino acids changes the relative spatial disposition of the DNA-binding domains and thereby disrupt the protein-DNA complex. Finally, we identified small molecules, including a tetrahydroquinoline carbonitrile derivative (S010-0261), that inhibit the MtbAldR-DNA complex. The latter molecules represent the very first inhibitors of a feast/famine regulatory protein from any source and set the stage for exploring MtbAldR as a potential anti-tuberculosis target. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Using naturally occurring polysaccharides to align molecules with nonlinear optical activity

NASA Technical Reports Server (NTRS)

Prasthofer, Thomas

1996-01-01

The Biophysics and Advanced Materials Branch of the Microgravity Science and Applications Division at Marshall Space Flight Center has been investigating polymers with the potential for nonlinear optical (NLO) applications for a number of years. Some of the potential applications for NLO materials include optical communications, computing, and switching. To this point the branch's research has involved polydiacetylenes, phthalocyanins, and other synthetic polymers which have inherent NLO properties. The aim of the present research is to investigate the possibility of using naturally occurring polymers such as polysaccharides or proteins to trap and align small organic molecules with useful NLO properties. Ordering molecules with NLO properties enhances 3rd order nonlinear effects and is required for 2nd order nonlinear effects. Potential advantages of such a system are the flexibility to use different small molecules with varying chemical and optical properties, the stability and cost of the polymers, and the ability to form thin, optically transparent films. Since the quality of any polymer films depends on optimizing ordering and minimizing defects, this work is particularly well suited for microgravity experiments. Polysaccharide and protein polymers form microscopic crystallites which must align to form ordered arrays. The ordered association of crystallites is disrupted by gravity effects and NASA research on protein crystal growth has demonstrated that low gravity conditions can improve crystal quality.

Crystallization of the Fab from a human monoclonal antibody against gp 41 of human immunodeficiency virus type I

NASA Technical Reports Server (NTRS)

Casale, Elena; He, Xiao-Min; Snyder, Robert S.; Carter, Daniel C.; Wenisch, Elisabeth; Jungbauer, Alois; Tauer, Christa; Ruker, Florian; Righetti, Pier Giorgio

1990-01-01

A monoclonal IgG antibody directed against gp 41 from the human immunodeficiency virus (HIV-1) has been crystallized in both intact and Fab forms. Crystals of the intact antibody grow as tetragonal-like prisms too small for conventional X-ray analysis. However, the Fab portion of the antibody produces suitable platelike crystals which belong to the space group P2(1)2(1)2(1) with unit cell constants of a = 66.5 A, b = 74.3 A, and c = 105.3 A. There is one molecule of Fab in the asymmetric unit. The Fab crystals show diffraction to d-spacings less than 3.0 A.

DG-AMMOS: a new tool to generate 3d conformation of small molecules using distance geometry and automated molecular mechanics optimization for in silico screening.

PubMed

Lagorce, David; Pencheva, Tania; Villoutreix, Bruno O; Miteva, Maria A

2009-11-13

Discovery of new bioactive molecules that could enter drug discovery programs or that could serve as chemical probes is a very complex and costly endeavor. Structure-based and ligand-based in silico screening approaches are nowadays extensively used to complement experimental screening approaches in order to increase the effectiveness of the process and facilitating the screening of thousands or millions of small molecules against a biomolecular target. Both in silico screening methods require as input a suitable chemical compound collection and most often the 3D structure of the small molecules has to be generated since compounds are usually delivered in 1D SMILES, CANSMILES or in 2D SDF formats. Here, we describe the new open source program DG-AMMOS which allows the generation of the 3D conformation of small molecules using Distance Geometry and their energy minimization via Automated Molecular Mechanics Optimization. The program is validated on the Astex dataset, the ChemBridge Diversity database and on a number of small molecules with known crystal structures extracted from the Cambridge Structural Database. A comparison with the free program Balloon and the well-known commercial program Omega generating the 3D of small molecules is carried out. The results show that the new free program DG-AMMOS is a very efficient 3D structure generator engine. DG-AMMOS provides fast, automated and reliable access to the generation of 3D conformation of small molecules and facilitates the preparation of a compound collection prior to high-throughput virtual screening computations. The validation of DG-AMMOS on several different datasets proves that generated structures are generally of equal quality or sometimes better than structures obtained by other tested methods.

High-Affinity Small-Molecule Inhibitors of the Menin-Mixed Lineage Leukemia (MLL) Interaction Closely Mimic a Natural Protein-Protein Interaction

DOE Office of Scientific and Technical Information (OSTI.GOV)

He, Shihan; Senter, Timothy J.; Pollock, Jonathan

2014-10-02

The protein–protein interaction (PPI) between menin and mixed lineage leukemia (MLL) plays a critical role in acute leukemias, and inhibition of this interaction represents a new potential therapeutic strategy for MLL leukemias. We report development of a novel class of small-molecule inhibitors of the menin–MLL interaction, the hydroxy- and aminomethylpiperidine compounds, which originated from HTS of ~288000 small molecules. We determined menin–inhibitor co-crystal structures and found that these compounds closely mimic all key interactions of MLL with menin. Extensive crystallography studies combined with structure-based design were applied for optimization of these compounds, resulting in MIV-6R, which inhibits the menin–MLL interactionmore » with IC 50 = 56 nM. Treatment with MIV-6 demonstrated strong and selective effects in MLL leukemia cells, validating specific mechanism of action. Our studies provide novel and attractive scaffold as a new potential therapeutic approach for MLL leukemias and demonstrate an example of PPI amenable to inhibition by small molecules.« less

Three-dimensional Structures of Carotenoids by X-ray Crystallography

NASA Astrophysics Data System (ADS)

Helliwell, Madeleine

The number of crystal structures of carotenoid molecules and carotenoid derivatives deposited in the Cambridge Crystallographic Data Centre [1] is still relatively small, but has increased compared with the previous survey [2]. The list is summarized in Table 1.

Inter-subunit electrostatic interactions in ferritin molecule: comparison with inter-molecular interactions in crystals

NASA Astrophysics Data System (ADS)

Takahashi, Takuya; Hogyoku, Michiru; Nagayama, Kuniaki

1996-10-01

We evaluated the contribution of electrostatic interactions to the stability of macromolecular assembly in a horse L ferritin molecule composed of 24 subunits and the three-dimensional crystal of the ferritin molecules with numerical calculation of Poisson-Boltzmann equation based on dielectric model. The calculation showed that the electrostatic energy both favors the assembly of the 24 subunits and the crystalline assembly of the ferritin molecules (i.e., 24-mers). Short-range interactions less than 5 Å such as salt bridges and hydrogen bonds were important for both the subunit assembly and the crystalline assembly. To elucidate the strong stabilization by electrostatic interactions in both the ferritin 24-mer and its crystal, we analyzed the contribution of individual atoms. It revealed that the stabilization was arising from buried salt bridges or hydrogen bonds, which yielded more than 5 kcal/mol in some interactions. These large electrostatic stabilization and also the unexpected small ionic strength dependence was different from those of bovine pancreatic trypsin inhibitor (BPTI) orthorhombic and pig-insulin cubic crystals previously calculated. We also evaluated changes of the accessible surface area (ASA) and hydration free energy in accordance with the process of the subunit assembly. The change of hydration free energy, which was very large (i.e. ˜ + 100 kcal/mol/subunit) and unfavorable for the assembly, was proportional to the electrostatic hydration energy (i.e. Born energy change in hydration process). Hydrophobic groups were likely to appear more frequently than hydrophilic groups at the subunit interfaces. These results suggest that the molecular structure of the ferritin 24-mer and the crystal structure of the 24-mers were both stabilized by local electrostatic interactions, in particular. We view protein crystals as an extension of the protein oligomer to an infinite number of subunits association.

Defect-induced solid state amorphization of molecular crystals

NASA Astrophysics Data System (ADS)

Lei, Lei; Carvajal, Teresa; Koslowski, Marisol

2012-04-01

We investigate the process of mechanically induced amorphization in small molecule organic crystals under extensive deformation. In this work, we develop a model that describes the amorphization of molecular crystals, in which the plastic response is calculated with a phase field dislocation dynamics theory in four materials: acetaminophen, sucrose, γ-indomethacin, and aspirin. The model is able to predict the fraction of amorphous material generated in single crystals for a given applied stress. Our results show that γ-indomethacin and sucrose demonstrate large volume fractions of amorphous material after sufficient plastic deformation, while smaller amorphous volume fractions are predicted in acetaminophen and aspirin, in agreement with experimental observation.

Polymer-Induced Heteronucleation for Protein Single Crystal Growth: Structural Elucidation of Bovine Liver Catalase and Concanavalin A Forms

DOE Office of Scientific and Technical Information (OSTI.GOV)

Foroughi, Leila M.; Kang, You-Na; Matzger, Adam J.

Obtaining single crystals for X-ray diffraction remains a major bottleneck in structural biology; when existing crystal growth methods fail to yield suitable crystals, often the target rather than the crystallization approach is reconsidered. Here we demonstrate that polymer-induced heteronucleation, a powerful technique that has been used for small molecule crystallization form discovery, can be applied to protein crystallization by optimizing the heteronucleant composition and crystallization formats for crystallizing a wide range of protein targets. Applying these advances to two benchmark proteins resulted in dramatically increased crystal size, enabling structure determination, for a half century old form of bovine liver catalasemore » (BLC) that had previously only been characterized by electron microscopy, and the discovery of two new forms of concanavalin A (conA) from the Jack bean and accompanying structural elucidation of one of these forms.« less

Advantages and application of label-free detection assays in drug screening.

PubMed

Cunningham, Brian T; Laing, Lance G

2008-08-01

Adoption is accelerating for a new family of label-free optical biosensors incorporated into standard format microplates owing to their ability to enable highly sensitive detection of small molecules, proteins and cells for high-throughput drug discovery applications. Label-free approaches are displacing other detection technologies owing to their ability to provide simple assay procedures for hit finding/validation, accessing difficult target classes, screening the interaction of cells with drugs and analyzing the affinity of small molecule inhibitors to target proteins. This review describes several new drug discovery applications that are under development for microplate-based photonic crystal optical biosensors and the key issues that will drive adoption of the technology. Microplate-based optical biosensors are enabling a variety of cell-based assays, inhibition assays, protein-protein binding assays and protein-small molecule binding assays to be performed with high-throughput and high sensitivity.

The trap DOS in small molecule organic semiconductors: A quantitative comparison of thin-film transistors with single crystals

NASA Astrophysics Data System (ADS)

Kalb, Wolfgang; Haas, Simon; Pernstich, Kurt; Mathis, Thomas; Batlogg, Bertram

2010-03-01

Our study shows that it is possible to reach one of the ultimate goals of organic electronics: organic field-effect transistors can be produced with trap densities as low as in the bulk of single crystals. Several analytical methods to calculate the spectral density of localized states in the band gap (trap DOS) from measured data were used to clarify, if the different methods lead to similar results. We then compared quantitatively trap DOS information from the literature, correcting for differences due to different calculation methods. In the bulk of single crystals the trap DOS is lower by several orders of magnitude than in thin films. The compilation of all data strongly suggests that structural defects at grain boundaries are the main cause of ``fast'' traps in TFT's made with vacuum-evaporated pentacene. For high-performance transistors made with small molecule semiconductors such as rubrene it is essential to reduce the dipolar disorder caused by water adsorbed on the gate dielectric. We will discuss to what degree band broadening due to the thermal fluctuations of the intermolecular transfer integral is reflected in the trap DOS very close (<0.15 eV) to the mobility edge.

Diffusion of vaporous guests into a seemingly non-porous organic crystal

DOE Office of Scientific and Technical Information (OSTI.GOV)

Herbert, Simon A.; Janiak, Agnieszka; Thallapally, Praveen K.

2014-10-07

In this research, the tetragonal apohost phase of p-tert-butyltetramethoxythiacalix[4]arene absorbs hydrochloric acid and iodine. These guest molecules occupy different sites in the solid-state structure -- either within the small intrinsic voids of the macrocycle or within the interstitial spaces between the host molecules. This study illustrates the dynamic deformation of the host, providing strong mechanistic insight into the diffusion of guests into this seemingly non-porous material.

Shift in the equilibrium between on and off states of the allosteric switch in Ras-GppNHp affected by small molecules and bulk solvent composition.

PubMed

Holzapfel, Genevieve; Buhrman, Greg; Mattos, Carla

2012-08-07

Ras GTPase cycles between its active GTP-bound form promoted by GEFs and its inactive GDP-bound form promoted by GAPs to affect the control of various cellular functions. It is becoming increasingly apparent that subtle regulation of the GTP-bound active state may occur through promotion of substates mediated by an allosteric switch mechanism that induces a disorder to order transition in switch II upon ligand binding at an allosteric site. We show with high-resolution structures that calcium acetate and either dithioerythritol (DTE) or dithiothreitol (DTT) soaked into H-Ras-GppNHp crystals in the presence of a moderate amount of poly(ethylene glycol) (PEG) can selectively shift the equilibrium to the "on" state, where the active site appears to be poised for catalysis (calcium acetate), or to what we call the "ordered off" state, which is associated with an anticatalytic conformation (DTE or DTT). We also show that the equilibrium is reversible in our crystals and dependent on the nature of the small molecule present. Calcium acetate binding in the allosteric site stabilizes the conformation observed in the H-Ras-GppNHp/NOR1A complex, and PEG, DTE, and DTT stabilize the anticatalytic conformation observed in the complex between the Ras homologue Ran and Importin-β. The small molecules are therefore selecting biologically relevant conformations in the crystal that are sampled by the disordered switch II in the uncomplexed GTP-bound form of H-Ras. In the presence of a large amount of PEG, the ordered off conformation predominates, whereas in solution, in the absence of PEG, switch regions appear to remain disordered in what we call the off state, unable to bind DTE.

Shift in the Equilibrium between On and Off States of the Allosteric Switch in Ras-GppNHp Affected by Small Molecules and Bulk Solvent Composition

DOE Office of Scientific and Technical Information (OSTI.GOV)

Holzapfel, Genevieve; Buhrman, Greg; Mattos, Carla

2012-08-31

Ras GTPase cycles between its active GTP-bound form promoted by GEFs and its inactive GDP-bound form promoted by GAPs to affect the control of various cellular functions. It is becoming increasingly apparent that subtle regulation of the GTP-bound active state may occur through promotion of substates mediated by an allosteric switch mechanism that induces a disorder to order transition in switch II upon ligand binding at an allosteric site. We show with high-resolution structures that calcium acetate and either dithioerythritol (DTE) or dithiothreitol (DTT) soaked into H-Ras-GppNHp crystals in the presence of a moderate amount of poly(ethylene glycol) (PEG) canmore » selectively shift the equilibrium to the 'on' state, where the active site appears to be poised for catalysis (calcium acetate), or to what we call the 'ordered off' state, which is associated with an anticatalytic conformation (DTE or DTT). We also show that the equilibrium is reversible in our crystals and dependent on the nature of the small molecule present. Calcium acetate binding in the allosteric site stabilizes the conformation observed in the H-Ras-GppNHp/NOR1A complex, and PEG, DTE, and DTT stabilize the anticatalytic conformation observed in the complex between the Ras homologue Ran and Importin-{beta}. The small molecules are therefore selecting biologically relevant conformations in the crystal that are sampled by the disordered switch II in the uncomplexed GTP-bound form of H-Ras. In the presence of a large amount of PEG, the ordered off conformation predominates, whereas in solution, in the absence of PEG, switch regions appear to remain disordered in what we call the off state, unable to bind DTE.« less

Fabrication and characterization of controllable grain boundary arrays in solution-processed small molecule organic semiconductor films

NASA Astrophysics Data System (ADS)

Wo, Songtao; Headrick, Randall L.; Anthony, John E.

2012-04-01

We have produced solution-processed thin films of 6,13-bis(tri-isopropyl-silylethynyl) pentacene with grain sizes from a few micrometers up to millimeter scale by lateral crystallization from a rectangular stylus. Grains are oriented along the crystallization direction, and the grain size transverse to the crystallization direction depends inversely on the writing speed, hence forming a regular array of oriented grain boundaries with controllable spacing. We utilize these controllable arrays to systematically study the role of large-angle grain boundaries in carrier transport and charge trapping in thin film transistors. The effective mobility scales with the grain size, leading to an estimate of the potential drop at individual large-angle grain boundaries of more than 1 volt. This result indicates that the structure of grain boundaries is not molecularly abrupt, which may be a general feature of solution-processed small molecule organic semiconductor thin films, where relatively high energy grain boundaries are typically formed. Transient measurements after switching from positive to negative gate bias or between large and small negative gate bias reveal reversible charge trapping, with time constants on the order of 10 s and trap densities that are correlated with grain boundary density. We suggest that charge diffusion along grain boundaries and other defects is the rate-determining mechanism of the reversible trapping.

Protein crystal growth in microgravity

NASA Technical Reports Server (NTRS)

Rosenblum, William M.; Delucas, Lawrence J.; Wilson, William W.

1989-01-01

Major advances have been made in several of the experimental aspects of protein crystallography, leaving protein crystallization as one of the few remaining bottlenecks. As a result, it has become important that the science of protein crystal growth is better understood and that improved methods for protein crystallization are developed. Preliminary experiments with both small molecules and proteins indicate that microgravity may beneficially affect crystal growth. For this reason, a series of protein crystal growth experiments using the Space Shuttle was initiated. The preliminary space experiments were used to evolve prototype hardware that will form the basis for a more advanced system that can be used to evaluate effects of gravity on protein crystal growth. Various optical techniques are being utilized to monitor the crystal growth process from the incipient or nucleation stage and throughout the growth phase. The eventual goal of these studies is to develop a system which utilizes optical monitoring for dynamic control of the crystallization process.

Liquid-crystal panel with microdots on an electrode used to modulate optical phase profiles.

PubMed

Kishima, Koichiro; Yoshida, Naoko; Osato, Kiyoshi; Nakagawa, Nobuyoshi

2006-05-20

The optical characteristics of a liquid-crystal (LC) panel with microdots on an electrode are investigated. Although 3 mum is larger than 1 molecule of LC material, microdots with a 3 microm diameter are sufficiently small to produce a smooth index profile. We use an electrode patterned in a new way to modulate the index profile of the LC panel, which allows us to modulate the optical phase of the passing light.

Hopper Growth of Salt Crystals.

PubMed

Desarnaud, Julie; Derluyn, Hannelore; Carmeliet, Jan; Bonn, Daniel; Shahidzadeh, Noushine

2018-06-07

The growth of hopper crystals is observed for many substances, but the mechanism of their formation remains ill understood. Here we investigate their growth by performing evaporation experiments on small volumes of salt solutions. We show that sodium chloride crystals that grow very fast from a highly supersaturated solution form a peculiar form of hopper crystal consisting of a series of connected miniature versions of the original cubic crystal. The transition between cubic and such hopper growth happens at a well-defined supersaturation where the growth rate of the cubic crystal reaches a maximum (∼6.5 ± 1.8 μm/s). Above this threshold, the growth rate varies as the third power of supersaturation, showing that a new mechanism, controlled by the maximum speed of surface integration of new molecules, induces the hopper growth of cubic crystals in cascade.

Development of a high-throughput crystal structure-determination platform for JAK1 using a novel metal-chelator soaking system

DOE Office of Scientific and Technical Information (OSTI.GOV)

Caspers, Nicole L.; Han, Seungil; Rajamohan, Francis

2016-10-27

Crystals of phosphorylated JAK1 kinase domain were initially generated in complex with nucleotide (ADP) and magnesium. The tightly bound Mg 2+-ADP at the ATP-binding site proved recalcitrant to ligand displacement. Addition of a molar excess of EDTA helped to dislodge the divalent metal ion, promoting the release of ADP and allowing facile exchange with ATP-competitive small-molecule ligands. Many kinases require the presence of a stabilizing ligand in the ATP site for crystallization. This procedure could be useful for developing co-crystallization systems with an exchangeable ligand to enable structure-based drug design of other protein kinases.

Spray printing of organic semiconducting single crystals

NASA Astrophysics Data System (ADS)

Rigas, Grigorios-Panagiotis; Payne, Marcia M.; Anthony, John E.; Horton, Peter N.; Castro, Fernando A.; Shkunov, Maxim

2016-11-01

Single-crystal semiconductors have been at the forefront of scientific interest for more than 70 years, serving as the backbone of electronic devices. Inorganic single crystals are typically grown from a melt using time-consuming and energy-intensive processes. Organic semiconductor single crystals, however, can be grown using solution-based methods at room temperature in air, opening up the possibility of large-scale production of inexpensive electronics targeting applications ranging from field-effect transistors and light-emitting diodes to medical X-ray detectors. Here we demonstrate a low-cost, scalable spray-printing process to fabricate high-quality organic single crystals, based on various semiconducting small molecules on virtually any substrate by combining the advantages of antisolvent crystallization and solution shearing. The crystals' size, shape and orientation are controlled by the sheer force generated by the spray droplets' impact onto the antisolvent's surface. This method demonstrates the feasibility of a spray-on single-crystal organic electronics.

Effects of Purification on the Crystallization of Lysozyme

NASA Technical Reports Server (NTRS)

Ewing, Felecia L.; Forsythe, Elizabeth L.; Van Der Woerd, Mark; Pusey, Marc L.

1996-01-01

We have additionally purified a commercial lysozyme preparation by cation exchange chromatography, followed by recrystallization. This material is 99.96% pure with respect to macromolecular impurities. At basic pH, the purified lysozyme gave only tetragonal crystals at 20 C. Protein used directly from the bottle, prepared by dialysis against distilled water, or which did not bind to the cation exchange column had considerably altered crystallization behavior. Lysozyme which did not bind to the cation exchange column was subsequently purified by size exclusion chromatography. This material gave predominately bundles of rod-shaped crystals with some small tetragonal crystals at lower pHs. The origin of the bundled rod habit was postulated to be a thermally dependent tetragonal- orthorhombic change in the protein structure. This was subsequently ruled out on the basis of crystallization behavior and growth rate experiments. This suggests that heterogeneous forms of lysozyme may be responsible. These results demonstrate three classes of impurities: (1) small molecules, which may be removed by dialysis; (2) macromolecules, which are removable by chromatographic techniques; and (3) heterogeneous forms of the protein, which can be removed in this case by cation exchange chromatography. Of these, heterogeneous forms of the lysozyme apparently have the greatest affect on its crystallization behavior.

Laser desorption/ionization mass spectrometry for direct profiling and imaging of small molecules from raw biological materials

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cha, Sangwon

2008-01-01

Matrix-assisted laser desorption/ionization(MALDI) mass spectrometry(MS) has been widely used for analysis of biological molecules, especially macromolecules such as proteins. However, MALDI MS has a problem in small molecule (less than 1 kDa) analysis because of the signal saturation by organic matrixes in the low mass region. In imaging MS (IMS), inhomogeneous surface formation due to the co-crystallization process by organic MALDI matrixes limits the spatial resolution of the mass spectral image. Therefore, to make laser desorption/ionization (LDI) MS more suitable for mass spectral profiling and imaging of small molecules directly from raw biological tissues, LDI MS protocols with various alternativemore » assisting materials were developed and applied to many biological systems of interest. Colloidal graphite was used as a matrix for IMS of small molecules for the first time and methodologies for analyses of small metabolites in rat brain tissues, fruits, and plant tissues were developed. With rat brain tissues, the signal enhancement for cerebroside species by colloidal graphite was observed and images of cerebrosides were successfully generated by IMS. In addition, separation of isobaric lipid ions was performed by imaging tandem MS. Directly from Arabidopsis flowers, flavonoids were successfully profiled and heterogeneous distribution of flavonoids in petals was observed for the first time by graphite-assisted LDI(GALDI) IMS.« less

Crystallization and X-ray diffraction analysis of salicylate synthase, a chorismate-utilizing enyme involved in siderophore biosynthesis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Parsons, James F., E-mail: parsonsj@umbi.umd.edu; Shi, Katherine; Calabrese, Kelly

2006-03-01

Salicylate synthase, which catalyzes the first step in the synthesis of the siderophore yersiniabactin, has been crystallized. Diffraction data have been collected to 2.5 Å. Bacteria have evolved elaborate schemes that help them thrive in environments where free iron is severely limited. Siderophores such as yersiniabactin are small iron-scavenging molecules that are deployed by bacteria during iron starvation. Several studies have linked siderophore production and virulence. Yersiniabactin, produced by several Enterobacteriaceae, is derived from the key metabolic intermediate chorismic acid via its conversion to salicylate by salicylate synthase. Crystals of salicylate synthase from the uropathogen Escherichia coli CFT073 have beenmore » grown by vapour diffusion using polyethylene glycol as the precipitant. The monoclinic (P2{sub 1}) crystals diffract to 2.5 Å. The unit-cell parameters are a = 57.27, b = 164.07, c = 59.04 Å, β = 108.8°. The solvent content of the crystals is 54% and there are two molecules of the 434-amino-acid protein in the asymmetric unit. It is anticipated that the structure will reveal key details about the reaction mechanism and the evolution of salicylate synthase.« less

X-ray Diffraction from Membrane Protein Nanocrystals

PubMed Central

Hunter, M.S.; DePonte, D.P.; Shapiro, D.A.; Kirian, R.A.; Wang, X.; Starodub, D.; Marchesini, S.; Weierstall, U.; Doak, R.B.; Spence, J.C.H.; Fromme, P.

2011-01-01

Membrane proteins constitute >30% of the proteins in an average cell, and yet the number of currently known structures of unique membrane proteins is <300. To develop new concepts for membrane protein structure determination, we have explored the serial nanocrystallography method, in which fully hydrated protein nanocrystals are delivered to an x-ray beam within a liquid jet at room temperature. As a model system, we have collected x-ray powder diffraction data from the integral membrane protein Photosystem I, which consists of 36 subunits and 381 cofactors. Data were collected from crystals ranging in size from 100 nm to 2 μm. The results demonstrate that there are membrane protein crystals that contain <100 unit cells (200 total molecules) and that 3D crystals of membrane proteins, which contain <200 molecules, may be suitable for structural investigation. Serial nanocrystallography overcomes the problem of x-ray damage, which is currently one of the major limitations for x-ray structure determination of small crystals. By combining serial nanocrystallography with x-ray free-electron laser sources in the future, it may be possible to produce molecular-resolution electron-density maps using membrane protein crystals that contain only a few hundred or thousand unit cells. PMID:21190672

Berkeley Screen: a set of 96 solutions for general macromolecular crystallization

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pereira, Jose H.; McAndrew, Ryan P.; Tomaleri, Giovani P.

Using statistical analysis of the Biological Macromolecular Crystallization Database, combined with previous knowledge about crystallization reagents, a crystallization screen called the Berkeley Screen has been created. Correlating crystallization conditions and high-resolution protein structures, it is possible to better understand the influence that a particular solution has on protein crystal formation. Ions and small molecules such as buffers and precipitants used in crystallization experiments were identified in electron density maps, highlighting the role of these chemicals in protein crystal packing. The Berkeley Screen has been extensively used to crystallize target proteins from the Joint BioEnergy Institute and the Collaborative Crystallography programmore » at the Berkeley Center for Structural Biology, contributing to several Protein Data Bank entries and related publications. The Berkeley Screen provides the crystallographic community with an efficient set of solutions for general macromolecular crystallization trials, offering a valuable alternative to the existing commercially available screens. The Berkeley Screen provides an efficient set of solutions for general macromolecular crystallization trials.« less

Berkeley Screen: a set of 96 solutions for general macromolecular crystallization

DOE PAGES

Pereira, Jose H.; McAndrew, Ryan P.; Tomaleri, Giovani P.; ...

2017-09-05

Using statistical analysis of the Biological Macromolecular Crystallization Database, combined with previous knowledge about crystallization reagents, a crystallization screen called the Berkeley Screen has been created. Correlating crystallization conditions and high-resolution protein structures, it is possible to better understand the influence that a particular solution has on protein crystal formation. Ions and small molecules such as buffers and precipitants used in crystallization experiments were identified in electron density maps, highlighting the role of these chemicals in protein crystal packing. The Berkeley Screen has been extensively used to crystallize target proteins from the Joint BioEnergy Institute and the Collaborative Crystallography programmore » at the Berkeley Center for Structural Biology, contributing to several Protein Data Bank entries and related publications. The Berkeley Screen provides the crystallographic community with an efficient set of solutions for general macromolecular crystallization trials, offering a valuable alternative to the existing commercially available screens. The Berkeley Screen provides an efficient set of solutions for general macromolecular crystallization trials.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stauber, Mark; Yeshiva University, 2495 Amsterdam Avenue, New York, NY 10033-3312; Jakoncic, Jean

Crystallization of lysozyme with (R)-2-methyl-2, 4-pentanediol produces more ordered crystals and a higher resolution protein structure than crystallization with (S)-2-methyl-2, 4-pentanediol. The results suggest that chiral interactions with chiral additives are important in protein crystal formation. Chiral control of crystallization has ample precedent in the small-molecule world, but relatively little is known about the role of chirality in protein crystallization. In this study, lysozyme was crystallized in the presence of the chiral additive 2-methyl-2, 4-pentanediol (MPD) separately using the R and S enantiomers as well as with a racemic RS mixture. Crystals grown with (R)-MPD had the most order andmore » produced the highest resolution protein structures. This result is consistent with the observation that in the crystals grown with (R)-MPD and (RS)-MPD the crystal contacts are made by (R)-MPD, demonstrating that there is preferential interaction between lysozyme and this enantiomer. These findings suggest that chiral interactions are important in protein crystallization.« less

Structure of bovine pancreatic ribonuclease complexed with uridine 5'-monophosphate at 1.60 A resolution.

PubMed

Larson, Steven B; Day, John S; Nguyen, Chieugiang; Cudney, Robert; McPherson, Alexander

2010-02-01

Bovine pancreatic ribonuclease A (RNase A) was crystallized from a mixture of small molecules containing basic fuchsin, tobramycin and uridine 5'-monophosphate (U5P). Solution of the crystal structure revealed that the enzyme was selectively bound to U5P, with the pyrimidine ring of U5P residing in the pyrimidine-binding site at Thr45. The structure was refined to an R factor of 0.197 and an R(free) of 0.253.

Novel Crystal Structure C60 Nanowire

NASA Astrophysics Data System (ADS)

Mickelson, William; Aloni, Shaul; Han, Weiqiang; Cumings, John; Zettl, Alex

2003-03-01

We have created insulated C60 nanowire by packing C60 molecules into the interior of insulating boron nitride (BN) nanotubes. For small-diameter BN tubes, the wire consists of a linear chain of C60's. With increasing BN tube inner diameter, novel C60 stacking configurations are obtained (including helical, hollow core, and incommensurate) which are unknown for bulk or thin film forms of C60. C60 in BN nanotubes presents a model system for studying the properties of new dimensionally-constrained "silo" crystal structures.

Growth of alkyl-monosubstituted thiophene/phenylene co-oligomer crystals and their device application

NASA Astrophysics Data System (ADS)

Sugahara, Kazuchika; Nakagawa, Takao; Hirase, Ryuji; Katagiri, Toshifumi; Inada, Yuhi; Yamao, Takeshi; Hotta, Shu

2018-04-01

We synthesized a novel small-molecule organic semiconductor, which is soluble in organic solvents at room temperature under normal pressure. We demonstrated that its high-quality crystalline films can be directly grown on substrates using various solution techniques such as solution casting, slow evaporation, and edge casting. We applied crystals to FETs with a bottom- or top-contact configuration, revealing that the carrier mobility ranged from ˜10-4 to ˜10-2 cm2 V-1 s-1.

Small Molecule Neuropilin-1 Antagonists Combine Antiangiogenic and Antitumor Activity with Immune Modulation through Reduction of Transforming Growth Factor Beta (TGFβ) Production in Regulatory T-Cells

PubMed Central

2018-01-01

We report the design, synthesis, and biological evaluation of some potent small-molecule neuropilin-1 (NRP1) antagonists. NRP1 is implicated in the immune response to tumors, particularly in Treg cell fragility, required for PD1 checkpoint blockade. The design of these compounds was based on a previously identified compound EG00229. The design of these molecules was informed and supported by X-ray crystal structures. Compound 1 (EG01377) was identified as having properties suitable for further investigation. Compound 1 was then tested in several in vitro assays and was shown to have antiangiogenic, antimigratory, and antitumor effects. Remarkably, 1 was shown to be selective for NRP1 over the closely related protein NRP2. In purified Nrp1+, FoxP3+, and CD25+ populations of Tregs from mice, 1 was able to block a glioma-conditioned medium-induced increase in TGFβ production. This comprehensive characterization of a small-molecule NRP1 antagonist provides the basis for future in vivo studies. PMID:29648813

Molecular dynamics study of structure H clathrate hydrates of methane and large guest molecules.

PubMed

Susilo, Robin; Alavi, Saman; Ripmeester, John A; Englezos, Peter

2008-05-21

Methane storage in structure H (sH) clathrate hydrates is attractive due to the relatively higher stability of sH as compared to structure I methane hydrate. The additional stability is gained without losing a significant amount of gas storage density as happens in the case of structure II (sII) methane clathrate. Our previous work has showed that the selection of a specific large molecule guest substance (LMGS) as the sH hydrate former is critical in obtaining the optimum conditions for crystallization kinetics, hydrate stability, and methane content. In this work, molecular dynamics simulations are employed to provide further insight regarding the dependence of methane occupancy on the type of the LMGS and pressure. Moreover, the preference of methane molecules to occupy the small (5(12)) or medium (4(3)5(6)6(3)) cages and the minimum cage occupancy required to maintain sH clathrate mechanical stability are examined. We found that thermodynamically, methane occupancy depends on pressure but not on the nature of the LMGS. The experimentally observed differences in methane occupancy for different LMGS may be attributed to the differences in crystallization kinetics and/or the nonequilibrium conditions during the formation. It is also predicted that full methane occupancies in both small and medium clathrate cages are preferred at higher pressures but these cages are not fully occupied at lower pressures. It was found that both small and medium cages are equally favored for occupancy by methane guests and at the same methane content, the system suffers a free energy penalty if only one type of cage is occupied. The simulations confirm the instability of the hydrate when the small and medium cages are empty. Hydrate decomposition was observed when less than 40% of the small and medium cages are occupied.

Effect of co-crystallization on singlet fission efficiency in pentacene derivatives

NASA Astrophysics Data System (ADS)

Wang, Xiaopeng; Sanders, Samuel; Campos, Luis; Sfeir, Matthew; Marom, Noa

Singlet fission (SF), the conversion of one singlet exciton into two triplet excitons, may lead to a twofold increase in the efficiency of organic photovoltaics. Since SF has been observed in crystalline pentacene, this material has drawn interest both experimentally and theoretically. Recently, it has been shown that SF efficiency in rubrene may be improved by modifying the crystal packing. Here, we study the effect of co-crystallization with small molecule H-bond donors on SF efficiency in pentacene derivatives. Five co-crystals are synthetized and their photoluminescence (PL) and absorption spectra are measured. First-principles calculations based on many-body perturbation theory (MBPT) are then employed to study their excitonic properties. By combining experiment and theory, we demonsrate that excitonic properties, including singlet-triplet gaps, exciton binding energies, and exciton localization, are significantly modulated in pentacene co-crystals. Consequently, co-crystallization becomes an effective strategy for improving SF efficiency in molecular crystals of organic semiconductors.

Growth Defects in Biomacromolecular Crystals

NASA Technical Reports Server (NTRS)

2003-01-01

NASA's ground based program confirmed close similarity between protein and small molecules crystal growth, but also revealed essential differences. No understanding exists as to why and when crystals grown in space are, in approx. 20 percent of cases, of higher quality. More rationale is needed in flight experiments. Ferritin crystals grown in space are 2.5 times cleaner than their terrestrial counterparts. This may occur because of the existence of a zone depleted with respect to impurities around a crystal growing in stagnant solution. This zone should appear since the distribution coefficient for homologous impurities exceeds unity. This impurity depletion zone hypothesis requires verification and development. Thorough purification from homologous impurities brought about resolution improvement from 2.6 to 1.8 angstroms for ferritin and from 2.6 to 2.0 angstroms for canavalin.

Crystal structure of NTPDase2 in complex with the sulfoanthraquinone inhibitor PSB-071.

PubMed

Zebisch, Matthias; Baqi, Younis; Schäfer, Petra; Müller, Christa E; Sträter, Norbert

2014-03-01

In many vertebrate tissues CD39-like ecto-nucleoside triphosphate diphosphohydrolases (NTPDases) act in concert with ecto-5'-nucleotidase (e5NT, CD73) to convert extracellular ATP to adenosine. Extracellular ATP is a cytotoxic, pro-inflammatory signalling molecule whereas its product adenosine constitutes a universal and potent immune suppressor. Interference with these ectonucleotidases by use of small molecule inhibitors or inhibitory antibodies appears to be an effective strategy to enhance anti-tumour immunity and suppress neoangiogenesis. Here we present the first crystal structures of an NTPDase catalytic ectodomain in complex with the Reactive Blue 2 (RB2)-derived inhibitor PSB-071. In both of the two crystal forms presented the inhibitor binds as a sandwich of two molecules at the nucleoside binding site. One of the molecules is well defined in its orientation. Specific hydrogen bonds are formed between the sulfonyl group and the nucleoside binding loop. The methylphenyl side chain functionality that improved NTPDase2-specificity is sandwiched between R245 and R394, the latter of which is exclusively found in NTPDase2. The second molecule exhibits great in-plane rotational freedom and could not be modelled in a specific orientation. In addition to this structural insight into NTPDase inhibition, the observation of the putative membrane interaction loop (MIL) in two different conformations related by a 10° rotation identifies the MIL as a dynamic section of NTPDases that is potentially involved in regulation of catalysis. Copyright © 2014 Elsevier Inc. All rights reserved.

Crystalline order of a water/glycine film coadsorbed on the (104) calcite surface.

PubMed

Magdans, Uta; Torrelles, Xavier; Angermund, Klaus; Gies, Hermann; Rius, Jordi

2007-04-24

For biomineralization processes, the interaction of the surface of calcite crystals with organic molecules is of particular importance. Especially, biologically controlled biomineralization as in exoskeletons of mollusks and echinoderms, e.g., sea urchin with single-crystal-like spines and shells,1-3 requires molecular control of seed formation and growth process. So far, experiments showing the obvious influence of organic molecules on the morphology and habit of calcite crystals have demonstrated the molecular dimension of the interaction.4-7 Details of the kinetics of growth and dissolution of mineral surfaces influenced by additives are available,8,9 but other experimental data about the structure of the organic/inorganic interface on the atomic scale are rare. On the other hand, complicated organic macromolecules which are involved in biomineralization are numerous, with only a small fraction solved in structure and function so far.10-13 Therefore, model systems have to be designed to provide a basic understanding for the interaction process.14 Using grazing incidence X-ray diffraction combined with molecular modeling techniques, we show that glycine molecules order periodically on the calcite (104) face in competition with the solvent water when exposed to an aqueous solution of the most simple amino acid. In contrast to the general concept of the charge-matching fit of organic molecules on mineral surfaces,4,14 glycine is not attached to the calcite surface directly but substitutes for water molecules in the second hydration layer.

Generation and use of high power 213 nm and 266 nm laser radiation and tunable 210-400 nm laser radiation with BBO crystal matrix array

DOEpatents

Gruen, Dieter M.

2000-01-01

A 213 nm laser beam is capable of single photon ablative photodecomposition for the removal of a polymer or biological material substrate. Breaking the molecular bonds and displacing the molecules away from the substrate in a very short time period results in most of the laser photon energy being carried away by the displaced molecules, thus minimizing thermal damage to the substrate. The incident laser beam may be unfocussed and is preferably produced by quintupling the 1064 nm radiation from a Nd:YAG solid state laser, i.e., at 213 nm. In one application, the 213 nm laser beam is expanded in cross section and directed through a plurality of small beta barium borate (BBO) crystals for increasing the energy per photon of the laser radiation directed onto the substrate. The BBO crystals are arranged in a crystal matrix array to provide a large laser beam transmission area capable of accommodating high energy laser radiation without damaging the BBO crystals. The BBO crystal matrix array may also be used with 266 nm laser radiation for carrying out single or multi photon ablative photodecomposition. The BBO crystal matrix array may also be used in an optical parametric oscillator mode to generate high power tunable laser radiation in the range of 210-400 nm.

Discovery of a 2,4-Diamino-7-aminoalkoxy-quinazoline as a Potent and Selective Inhibitor of Histone Lysine Methyltransferase G9a†

PubMed Central

Liu, Feng; Chen, Xin; Allali-Hassani, Abdellah; Quinn, Amy M.; Wasney, Gregory A.; Dong, Aiping; Barsyte, Dalia; Kozieradzki, Ivona; Senisterra, Guillermo; Chau, Irene; Siarheyeva, Alena; Kireev, Dmitri B.; Jadhav, Ajit; Herold, J. Martin; Frye, Stephen V.; Arrowsmith, Cheryl H.; Brown, Peter J.; Simeonov, Anton; Vedadi, Masoud; Jin, Jian

2010-01-01

SAR exploration of the 2,4-diamino-6,7-dimethoxyquinazoline template led to the discovery of 8 (UNC0224) as a potent and selective G9a inhibitor. A high resolution X-ray crystal structure of the G9a-8 complex, the first co-crystal structure of G9a with a small molecule inhibitor, was obtained. The co-crystal structure validated our binding hypothesis and will enable structure-based design of novel inhibitors. 8 is a useful tool for investigating the biology of G9a and its roles in chromatin remodeling. PMID:19891491

Alteration of fluorescent protein spectroscopic properties upon cryoprotection.

PubMed

von Stetten, David; Batot, Gaëlle O; Noirclerc-Savoye, Marjolaine; Royant, Antoine

2012-11-01

Cryoprotection of a protein crystal by addition of small-molecule compounds may sometimes affect the structure of its active site. The spectroscopic and structural effects of the two cryoprotectants glycerol and ethylene glycol on the cyan fluorescent protein Cerulean were investigated. While glycerol had almost no noticeable effect, ethylene glycol was shown to induce a systematic red shift of the UV-vis absorption and fluorescence emission spectra. Additionally, ethylene glycol molecules were shown to enter the core of the protein, with one of them binding in close vicinity to the chromophore, which provides a sound explanation for the observed spectroscopic changes. These results highlight the need to systematically record spectroscopic data on crystals of light-absorbing proteins and reinforce the notion that fluorescent proteins must not been seen as rigid structures.

Small Molecule Ligands of Methyl-Lysine Binding Proteins

PubMed Central

Herold, J. Martin; Wigle, Tim J.; Norris, Jacqueline L.; Lam, Robert; Korboukh, Victoria K.; Gao, Cen; Ingerman, Lindsey A.; Kireev, Dmitri B.; Senisterra, Guillermo; Vedadi, Masoud; Tripathy, Ashutosh; Brown, Peter J.; Arrowsmith, Cheryl H.; Jin, Jian; Janzen, William P.; Frye, Stephen V.

2011-01-01

Proteins which bind methylated lysines (“readers” of the histone code) are important components in the epigenetic regulation of gene expression and can also modulate other proteins that contain methyl-lysine such as p53 and Rb. Recognition of methyl-lysine marks by MBT domains leads to compaction of chromatin and a repressed transcriptional state. Antagonists of MBT domains would serve as probes to interrogate the functional role of these proteins and initiate the chemical biology of methyl-lysine readers as a target class. Small molecule MBT antagonists were designed based on the structure of histone peptide-MBT complexes and their interaction with MBT domains determined using a chemiluminescent assay and ITC. The ligands discovered antagonize native histone peptide binding, exhibiting 5-fold stronger binding affinity to L3MBTL1 than its preferred histone peptide. The first co-crystal structure of a small molecule bound to L3MBTL1 was determined and provides new insights into binding requirements for further ligand design. PMID:21417280

Small Molecule Inhibition of Ligand-Stimulated RAGE-DIAPH1 Signal Transduction

PubMed Central

Manigrasso, Michaele B.; Pan, Jinhong; Rai, Vivek; Zhang, Jinghua; Reverdatto, Sergey; Quadri, Nosirudeen; DeVita, Robert J.; Ramasamy, Ravichandran; Shekhtman, Alexander; Schmidt, Ann Marie

2016-01-01

The receptor for advanced glycation endproducts (RAGE) binds diverse ligands linked to chronic inflammation and disease. NMR spectroscopy and x-ray crystallization studies of the extracellular domains of RAGE indicate that RAGE ligands bind by distinct charge- and hydrophobicity-dependent mechanisms. The cytoplasmic tail (ct) of RAGE is essential for RAGE ligand-mediated signal transduction and consequent modulation of gene expression and cellular properties. RAGE signaling requires interaction of ctRAGE with the intracellular effector, mammalian diaphanous 1 or DIAPH1. We screened a library of 58,000 small molecules and identified 13 small molecule competitive inhibitors of ctRAGE interaction with DIAPH1. These compounds, which exhibit in vitro and in vivo inhibition of RAGE-dependent molecular processes, present attractive molecular scaffolds for the development of therapeutics against RAGE-mediated diseases, such as those linked to diabetic complications, Alzheimer’s disease, and chronic inflammation, and provide support for the feasibility of inhibition of protein-protein interaction (PPI). PMID:26936329

Design and Discovery of N -(2-Methyl-5'-morpholino-6'-((tetrahydro-2 H -pyran-4-yl)oxy)-[3,3'-bipyridin]-5-yl)-3-(trifluoromethyl)benzamide (RAF709): A Potent, Selective, and Efficacious RAF Inhibitor Targeting RAS Mutant Cancers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nishiguchi, Gisele A.; Rico, Alice; Tanner, Huw

RAS oncogenes have been implicated in >30% of human cancers, all representing high unmet medical need. The exquisite dependency on CRAF kinase in KRAS mutant tumors has been established in genetically engineered mouse models and human tumor cells. To date, many small molecule approaches are under investigation to target CRAF, yet kinase-selective and cellular potent inhibitors remain challenging to identify. Herein, we describe 14 (RAF709) [Aversa, Biaryl amide compounds as kinase inhibitors and their preparation. WO 2014151616, 2014], a selective B/C RAF inhibitor, which was developed through a hypothesis-driven approach focusing on drug-like properties. A key challenge encountered in themore » medicinal chemistry campaign was maintaining a balance between good solubility and potent cellular activity (suppression of pMEK and proliferation) in KRAS mutant tumor cell lines. We investigated the small molecule crystal structure of lead molecule 7 and hypothesized that disruption of the crystal packing would improve solubility, which led to a change from N-methylpyridone to a tetrahydropyranyl oxy-pyridine derivative. 14 proved to be soluble, kinase selective, and efficacious in a KRAS mutant xenograft model.« less

Hydration-induced crystalline transformation of starch polymer under ambient conditions.

PubMed

Qiao, Dongling; Zhang, Binjia; Huang, Jing; Xie, Fengwei; Wang, David K; Jiang, Fatang; Zhao, Siming; Zhu, Jie

2017-10-01

With synchrotron small/wide-angle X-ray scattering (SAXS/WAXS), we revealed that post-harvest hydration at ambient conditions can further alter the starch crystalline structure. The hydration process induced the alignment of starch helices into crystalline lamellae, irrespective of the starch type (A- or B-). In this process, non-crystalline helices were probably packed with water molecules to form new crystal units, thereby enhancing the overall concentration of starch crystallinity. In particular, a fraction of the monoclinic crystal units of the A-type starches encapsulated water molecules during hydration, leading to the outward movement of starch helices. Such movement resulted in the transformation of monoclinic units into hexagonal units, which was associated with the B-type crystallites. Hence, the hydration under ambient conditions could enhance the B-polymorphic features for both A-type and B-type starches. The new knowledge obtained here may guide the design of biopolymer-based liquid crystal materials with controlled lattice regularity and demanded features. Copyright © 2017 Elsevier B.V. All rights reserved.

Microgravity

NASA Image and Video Library

2001-01-24

This photo shows the Handheld Diffusion Test Cell (HH-DTC) apparatus flown on the Space Shuttle. Similar cells (inside the plastic box) will be used in the Observable Protein Crystal Growth Apparatus (OPCGA) to be operated aboard the International Space Station (ISS). The principal investigator is Dr. Alex McPherson of the University of California, Irvine. Each individual cell comprises two sample chambers with a rotating center section that isolates the two from each other until the start of the experiment and after it is completed. The cells are made from optical-quality quartz glass to allow photography and interferometric observations. Each cell has a small light-emitting diode and lens to back-light the solution. In protein crystal growth experiments, a precipitating agent such as a salt solution is used to absorb and hold water but repel the protein molecules. This increases the concentration of protein until the molecules nucleate to form crystals. This cell is one of 96 that make up the experiment module portion of the OPCGA.

Microgravity

NASA Image and Video Library

2001-01-24

This photo shows an individual cell from the Handheld Diffusion Test Cell (HH-DTC) apparatus flown on the Space Shuttle. Similar cells will be used in the Observable Protein Crystal Growth Apparatus (OPCGA) to be operated aboard the International Space Station (ISS). The principal investigator is Dr. Alex McPherson of the University of California, Irvine. Each individual cell comprises two sample chambers with a rotating center section that isolates the two from each other until the start of the experiment and after it is completed. The cells are made from optical-quality quartz glass to allow photography and interferometric observations. Each cell has a small light-emitting diode and lens to back-light the solution. In protein crystal growth experiments, a precipitating agent such as a salt solution is used to absorb and hold water but repel the protein molecules. This increases the concentration of protein until the molecules nucleate to form crystals. This cell is one of 96 that make up the experiment module portion of the OPCGA.

Handheld Diffusion Test Cells

NASA Technical Reports Server (NTRS)

2001-01-01

This photo shows the Handheld Diffusion Test Cell (HH-DTC) apparatus flown on the Space Shuttle. Similar cells (inside the plastic box) will be used in the Observable Protein Crystal Growth Apparatus (OPCGA) to be operated aboard the International Space Station (ISS). The principal investigator is Dr. Alex McPherson of the University of California, Irvine. Each individual cell comprises two sample chambers with a rotating center section that isolates the two from each other until the start of the experiment and after it is completed. The cells are made from optical-quality quartz glass to allow photography and interferometric observations. Each cell has a small light-emitting diode and lens to back-light the solution. In protein crystal growth experiments, a precipitating agent such as a salt solution is used to absorb and hold water but repel the protein molecules. This increases the concentration of protein until the molecules nucleate to form crystals. This cell is one of 96 that make up the experiment module portion of the OPCGA.

Handheld Diffusion Test Cells

NASA Technical Reports Server (NTRS)

2001-01-01

This photo shows an individual cell from the Handheld Diffusion Test Cell (HH-DTC) apparatus flown on the Space Shuttle. Similar cells will be used in the Observable Protein Crystal Growth Apparatus (OPCGA) to be operated aboard the International Space Station (ISS). The principal investigator is Dr. Alex McPherson of the University of California, Irvine. Each individual cell comprises two sample chambers with a rotating center section that isolates the two from each other until the start of the experiment and after it is completed. The cells are made from optical-quality quartz glass to allow photography and interferometric observations. Each cell has a small light-emitting diode and lens to back-light the solution. In protein crystal growth experiments, a precipitating agent such as a salt solution is used to absorb and hold water but repel the protein molecules. This increases the concentration of protein until the molecules nucleate to form crystals. This cell is one of 96 that make up the experiment module portion of the OPCGA.

The Crystal Structure Analysis of Group B Streptococcus Sortase C1: A Model for the ;Lid; Movement upon Substrate Binding

DOE Office of Scientific and Technical Information (OSTI.GOV)

Khare, Baldeep; Fu, Zheng-Qing; Huang, I-Hsiu

2012-02-07

A unique feature of the class-C-type sortases, enzymes essential for Gram-positive pilus biogenesis, is the presence of a flexible 'lid' anchored in the active site. However, the mechanistic details of the 'lid' displacement, suggested to be a critical prelude for enzyme catalysis, are not yet known. This is partly due to the absence of enzyme-substrate and enzyme-inhibitor complex crystal structures. We have recently described the crystal structures of the Streptococcus agalactiae SAG2603 V/R sortase SrtC1 in two space groups (type II and type III) and that of its 'lid' mutant and proposed a role of the 'lid' as a protectormore » of the active-site hydrophobic environment. Here, we report the crystal structures of SAG2603 V/R sortase C1 in a different space group (type I) and that of its complex with a small-molecule cysteine protease inhibitor. We observe that the catalytic Cys residue is covalently linked to the small-molecule inhibitor without lid displacement. However, the type I structure provides a view of the sortase SrtC1 lid displacement while having structural elements similar to a substrate sorting motif suitably positioned in the active site. We propose that these major conformational changes seen in the presence of a substrate mimic in the active site may represent universal features of class C sortase substrate recognition and enzyme activation.« less

A DNA Crystal Designed to Contain Two Molecules per Asymmetric Unit

DOE Office of Scientific and Technical Information (OSTI.GOV)

T Wang; R Sha; J Birktoft

2011-12-31

We describe the self-assembly of a DNA crystal that contains two tensegrity triangle molecules per asymmetric unit. We have used X-ray crystallography to determine its crystal structure. In addition, we have demonstrated control over the colors of the crystals by attaching either Cy3 dye (pink) or Cy5 dye (blue-green) to the components of the crystal, yielding crystals of corresponding colors. Attaching the pair of dyes to the pair of molecules yields a purple crystal.

Hierarchical CaCO3 chromatography: a stationary phase based on biominerals.

PubMed

Sato, Kosuke; Oaki, Yuya; Takahashi, Daisuke; Toshima, Kazunobu; Imai, Hiroaki

2015-03-23

In biomineralization, acidic macromolecules play important roles for the growth control of crystals through a specific interaction. Inspired by this interaction, we report on an application of the hierarchical structures in CaCO3 biominerals to a stationary phase of chromatography. The separation and purification of acidic small organic molecules are achieved by thin-layer chromatography and flash chromatography using the powder of biominerals as the stationary phase. The unit nanocrystals and their oriented assembly, the hierarchical structure, are suitable for the adsorption site of the target organic molecules and the flow path of the elution solvents, respectively. The separation mode is ascribed to the specific adsorption of the acidic molecules on the crystal face and the coordination of the functional groups to the calcium ions. The results imply that a new family of stationary phase of chromatography can be developed by the fine tuning of hierarchical structures in CaCO3 materials. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Determination of the Molecular Structures of Ferric Enterobactin and Ferric Enantioenterobactin Using Racemic Crystallography.

PubMed

Johnstone, Timothy C; Nolan, Elizabeth M

2017-10-25

Enterobactin is a secondary metabolite produced by Enterobacteriaceae for acquiring iron, an essential metal nutrient. The biosynthesis and utilization of enterobactin permits many Gram-negative bacteria to thrive in environments where low soluble iron concentrations would otherwise preclude survival. Despite extensive work carried out on this celebrated molecule since its discovery over 40 years ago, the ferric enterobactin complex has eluded crystallographic structural characterization. We report the successful growth of single crystals containing ferric enterobactin using racemic crystallization, a method that involves cocrystallization of a chiral molecule with its mirror image. The structures of ferric enterobactin and ferric enantioenterobactin obtained in this work provide a definitive assignment of the stereochemistry at the metal center and reveal secondary coordination sphere interactions. The structures were employed in computational investigations of the interactions of these complexes with two enterobactin-binding proteins, which illuminate the influence of metal-centered chirality on these interactions. This work highlights the utility of small-molecule racemic crystallography for obtaining elusive structures of coordination complexes.

Phase diagram of a crystalline protein: Determination of the solubility of concanavalin A by a microquantitation assay

NASA Astrophysics Data System (ADS)

Mikol, Vincent; Giegé, Richard

1989-09-01

A quick and miniature method has been devised for determining protein solubility and used to investigate the equilibrium solubility of concanavalin A from the Jack Bean with its crystals as a function of ammonium sulfate concentration, temperature and pH. The crystals were characterized by X-ray diffraction and their morphologies related to the corresponding solubilities. The protein solution concentration was estimated out of small crystallizing drops using a rapid and sensitive microassay. Measurements of protein quantity were carried out in 96-well microplates in an automatic spectrophotometer. The resulting phase diagram has permitted to analyse the solubility of concanavalin A, to estimate supersaturation and to devise readily new ways of crystal growth of this lectin, namely by pH and temperature variations. Moreover, the approach is proved to be a valuable tool to design crystallization experiments of new molecules and to improve and control protein crystal growth.

Disappearing Enantiomorphs: Single Handedness in Racemate Crystals.

PubMed

Parschau, Manfred; Ernst, Karl-Heinz

2015-11-23

Although crystallization is the most important method for the separation of enantiomers of chiral molecules in the chemical industry, the chiral recognition involved in this process is poorly understood at the molecular level. We report on the initial steps in the formation of layered racemate crystals from a racemic mixture, as observed by STM at submolecular resolution. Grown on a copper single-crystal surface, the chiral hydrocarbon heptahelicene formed chiral racemic lattice structures within the first layer. In the second layer, enantiomerically pure domains were observed, underneath which the first layer contained exclusively the other enantiomer. Hence, the system changed from a 2D racemate into a 3D racemate with enantiomerically pure layers after exceeding monolayer-saturation coverage. A chiral bias in form of a small enantiomeric excess suppressed the crystallization of one double-layer enantiomorph so that the pure minor enantiomer crystallized only in the second layer. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Bio-inspired formation of functional calcite/metal oxide nanoparticle composites.

PubMed

Kim, Yi-Yeoun; Schenk, Anna S; Walsh, Dominic; Kulak, Alexander N; Cespedes, Oscar; Meldrum, Fiona C

2014-01-21

Biominerals are invariably composite materials, where occlusion of organic macromolecules within single crystals can significantly modify their properties. In this article, we take inspiration from this biogenic strategy to generate composite crystals in which magnetite (Fe3O4) and zincite (ZnO) nanoparticles are embedded within a calcite single crystal host, thereby endowing it with new magnetic or optical properties. While growth of crystals in the presence of small molecules, macromolecules and particles can lead to their occlusion within the crystal host, this approach requires particles with specific surface chemistries. Overcoming this limitation, we here precipitate crystals within a nanoparticle-functionalised xyloglucan gel, where gels can also be incorporated within single crystals, according to their rigidity. This method is independent of the nanoparticle surface chemistry and as the gel maintains its overall structure when occluded within the crystal, the nanoparticles are maintained throughout the crystal, preventing, for example, their movement and accumulation at the crystal surface during crystal growth. This methodology is expected to be quite general, and could be used to endow a wide range of crystals with new functionalities.

Packing C60 in Boron Nitride Nanotubes

NASA Astrophysics Data System (ADS)

Mickelson, W.; Aloni, S.; Han, Wei-Qiang; Cumings, John; Zettl, A.

2003-04-01

We have created insulated C60 nanowire by packing C60 molecules into the interior of insulating boron nitride nanotubes (BNNTs). For small-diameter BNNTs, the wire consists of a linear chain of C60 molecules. With increasing BNNT inner diameter, unusual C60 stacking configurations are obtained (including helical, hollow core, and incommensurate) that are unknown for bulk or thin-film forms of C60. C60 in BNNTs thus presents a model system for studying the properties of dimensionally constrained ``silo'' crystal structures. For the linear-chain case, we have fused the C60 molecules to form a single-walled carbon nanotube inside the insulating BNNT.

Method For Screening Microcrystallizations For Crystal Formation

DOEpatents

Santarsiero, Bernard D. , Stevens, Raymond C. , Schultz, Peter G. , Jaklevic, Joseph M. , Yegian, Derek T. , Cornell, Earl W. , Nordmeyer, Robert A.

2003-10-07

A method is provided for performing array microcrystallizations to determine suitable crystallization conditions for a molecule, the method comprising: forming an array of microcrystallizations, each microcrystallization comprising a drop comprising a mother liquor solution whose composition varies within the array and a molecule to be crystallized, the drop having a volume of less than 1 microliter; storing the array of microcrystallizations under conditions suitable for molecule crystals to form in the drops in the array; and detecting molecule crystal formation in the drops by taking images of the drops.

Decoding Corticotropin-Releasing Factor Receptor Type 1 Crystal 
Structures

PubMed Central

Doré, Andrew S.; Bortolato, Andrea; Hollenstein, Kaspar; Cheng, Robert K.Y.; Read, Randy J.; Marshall, Fiona H.

2017-01-01

The structural analysis of class B G protein-coupled receptors (GPCR), cell surface proteins responding to peptide hormones, has until recently been restricted to the extracellular domain (ECD). Cor-ticotropin-releasing factor receptor type 1 (CRF1R) is a class B receptor mediating stress response and also considered a drug target for depression and anxiety. Here we report the crystal structure of the trans-membrane domain of human CRF1R in complex with the small-molecule antagonist CP-376395 in a hex-agonal setting with translational non-crystallographic symmetry. Molecular dynamics and metadynamics simulations on this novel structure and the existing TMD structure for CRF1R provides insight as to how the small molecule ligand gains access to the induced-fit allosteric binding site with implications for the observed selectivity against CRF2R. Furthermore, molecular dynamics simulations performed using a full-length receptor model point to key interactions between the ECD and extracellular loop 3 of the TMD providing insight into the full inactive state of multidomain class B GPCRs. PMID:28183242

Protein Crystallization: Specific Phenomena and General Insights on Crystallization Kinetics

NASA Technical Reports Server (NTRS)

Rosenberger, F.

1998-01-01

Experimental and simulation studies of the nucleation and growth kinetics of proteins have revealed phenomena that are specific for macromolecular crystallization, and others that provide a more detailed understanding of solution crystallization in general. The more specific phenomena, which include metastable liquid-liquid phase separations and gelation prior to solid nucleation, are due to the small ratio of the intermolecular interaction-range to the size of molecules involved. The apparently more generally applicable mechanisms include the cascade-like formation of macrosteps, as an intrinsic morphological instability that roots in the coupled bulk transport and nonlinear interface kinetics in systems with mixed growth rate control. Analyses of this nonlinear response provide (a) criteria for the choice of bulk transport conditions to minimize structural defect formation, and (b) indications that the "slow" protein crystallization kinetics stems from the mutual retardation of growth steps.

Fragment-based virtual screening approach and molecular dynamics simulation studies for identification of BACE1 inhibitor leads.

PubMed

Manoharan, Prabu; Ghoshal, Nanda

2018-05-01

Traditional structure-based virtual screening method to identify drug-like small molecules for BACE1 is so far unsuccessful. Location of BACE1, poor Blood Brain Barrier permeability and P-glycoprotein (Pgp) susceptibility of the inhibitors make it even more difficult. Fragment-based drug design method is suitable for efficient optimization of initial hit molecules for target like BACE1. We have developed a fragment-based virtual screening approach to identify/optimize the fragment molecules as a starting point. This method combines the shape, electrostatic, and pharmacophoric features of known fragment molecules, bound to protein conjugate crystal structure, and aims to identify both chemically and energetically feasible small fragment ligands that bind to BACE1 active site. The two top-ranked fragment hits were subjected for a 53 ns MD simulation. Principle component analysis and free energy landscape analysis reveal that the new ligands show the characteristic features of established BACE1 inhibitors. The potent method employed in this study may serve for the development of potential lead molecules for BACE1-directed Alzheimer's disease therapeutics.

Heterogeneous distribution of dye-labelled biomineralizaiton proteins in calcite crystals

NASA Astrophysics Data System (ADS)

Liu, Chuang; Xie, Liping; Zhang, Rongqing

2015-12-01

Biominerals are highly ordered crystals mediated by organic matters especially proteins in organisms. However, how specific proteins are distributed inside biominerals are not well understood. In the present study, we use fluorescein isothiocyanate (FITC) to label extracted proteins from the shells of bivalve Pinctada fucata. By confocal laser scanning microscopy (CLSM), we observe a heterogeneous distribution of dye-labelled proteins inside synthetic calcite at the microscale. Proteins from the prismatic calcite layers accumulate at the edge of crystals while proteins from the nacreous aragonite layers accumulate at the center of crystals. Raman and X-ray powder diffraction show that both the proteins cannot alter the crystal phase. Scanning electron microscope demonstrates both proteins are able to affect the crystal morphology. This study may provide a direct approach for the visualization of protein distributions in crystals by small-molecule dye-labelled proteins as the additives in the crystallization process and improve our understanding of intracrystalline proteins distribution in biogenic calcites.

Practical quantum mechanics-based fragment methods for predicting molecular crystal properties.

PubMed

Wen, Shuhao; Nanda, Kaushik; Huang, Yuanhang; Beran, Gregory J O

2012-06-07

Significant advances in fragment-based electronic structure methods have created a real alternative to force-field and density functional techniques in condensed-phase problems such as molecular crystals. This perspective article highlights some of the important challenges in modeling molecular crystals and discusses techniques for addressing them. First, we survey recent developments in fragment-based methods for molecular crystals. Second, we use examples from our own recent research on a fragment-based QM/MM method, the hybrid many-body interaction (HMBI) model, to analyze the physical requirements for a practical and effective molecular crystal model chemistry. We demonstrate that it is possible to predict molecular crystal lattice energies to within a couple kJ mol(-1) and lattice parameters to within a few percent in small-molecule crystals. Fragment methods provide a systematically improvable approach to making predictions in the condensed phase, which is critical to making robust predictions regarding the subtle energy differences found in molecular crystals.

Small-molecule ligand docking into comparative models with Rosetta

PubMed Central

Combs, Steven A; DeLuca, Samuel L; DeLuca, Stephanie H; Lemmon, Gordon H; Nannemann, David P; Nguyen, Elizabeth D; Willis, Jordan R; Sheehan, Jonathan H; Meiler, Jens

2017-01-01

Structure-based drug design is frequently used to accelerate the development of small-molecule therapeutics. Although substantial progress has been made in X-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy, the availability of high-resolution structures is limited owing to the frequent inability to crystallize or obtain sufficient NMR restraints for large or flexible proteins. Computational methods can be used to both predict unknown protein structures and model ligand interactions when experimental data are unavailable. This paper describes a comprehensive and detailed protocol using the Rosetta modeling suite to dock small-molecule ligands into comparative models. In the protocol presented here, we review the comparative modeling process, including sequence alignment, threading and loop building. Next, we cover docking a small-molecule ligand into the protein comparative model. In addition, we discuss criteria that can improve ligand docking into comparative models. Finally, and importantly, we present a strategy for assessing model quality. The entire protocol is presented on a single example selected solely for didactic purposes. The results are therefore not representative and do not replace benchmarks published elsewhere. We also provide an additional tutorial so that the user can gain hands-on experience in using Rosetta. The protocol should take 5–7 h, with additional time allocated for computer generation of models. PMID:23744289

Targeting Cullin–RING E3 ubiquitin ligases for drug discovery: structure, assembly and small-molecule modulation

PubMed Central

Bulatov, Emil; Ciulli, Alessio

2015-01-01

In the last decade, the ubiquitin–proteasome system has emerged as a valid target for the development of novel therapeutics. E3 ubiquitin ligases are particularly attractive targets because they confer substrate specificity on the ubiquitin system. CRLs [Cullin–RING (really interesting new gene) E3 ubiquitin ligases] draw particular attention, being the largest family of E3s. The CRLs assemble into functional multisubunit complexes using a repertoire of substrate receptors, adaptors, Cullin scaffolds and RING-box proteins. Drug discovery targeting CRLs is growing in importance due to mounting evidence pointing to significant roles of these enzymes in diverse biological processes and human diseases, including cancer, where CRLs and their substrates often function as tumour suppressors or oncogenes. In the present review, we provide an account of the assembly and structure of CRL complexes, and outline the current state of the field in terms of available knowledge of small-molecule inhibitors and modulators of CRL activity. A comprehensive overview of the reported crystal structures of CRL subunits, components and full-size complexes, alone or with bound small molecules and substrate peptides, is included. This information is providing increasing opportunities to aid the rational structure-based design of chemical probes and potential small-molecule therapeutics targeting CRLs. PMID:25886174

Structure-Activity Relationships of Small Molecule Autotaxin Inhibitors with a Discrete Binding Mode.

PubMed

Miller, Lisa M; Keune, Willem-Jan; Castagna, Diana; Young, Louise C; Duffy, Emma L; Potjewyd, Frances; Salgado-Polo, Fernando; Engel García, Paloma; Semaan, Dima; Pritchard, John M; Perrakis, Anastassis; Macdonald, Simon J F; Jamieson, Craig; Watson, Allan J B

2017-01-26

Autotaxin (ATX) is a secreted enzyme responsible for the hydrolysis of lysophosphatidylcholine (LPC) to the bioactive lysophosphatidic acid (LPA) and choline. The ATX-LPA signaling pathway is implicated in cell survival, migration, and proliferation; thus, the inhibition of ATX is a recognized therapeutic target for a number of diseases including fibrotic diseases, cancer, and inflammation, among others. Many of the developed synthetic inhibitors for ATX have resembled the lipid chemotype of the native ligand; however, a small number of inhibitors have been described that deviate from this common scaffold. Herein, we report the structure-activity relationships (SAR) of a previously reported small molecule ATX inhibitor. We show through enzyme kinetics studies that analogues of this chemotype are noncompetitive inhibitors, and by using a crystal structure with ATX we confirm the discrete binding mode.

Can Csbnd H⋯Fsbnd C hydrogen bonds alter crystal packing features in the presence of Nsbnd H⋯Odbnd C hydrogen bond?

NASA Astrophysics Data System (ADS)

Yadav, Hare Ram; Choudhury, Angshuman Roy

2017-12-01

Intermolecular interactions involving organic fluorine have been the contemporary field of research in the area of organic solid state chemistry. While a group of researchers had refuted the importance of "organic fluorine" in guiding crystal structures, others have provided evidences for in favor of fluorine mediated interactions in the solid state. Many systematic studies have indicated that the "organic fluorine" is capable of offering weak hydrogen bonds through various supramolecular synthons, mostly in the absence of other stronger hydrogen bonds. Analysis of fluorine mediated interaction in the presence of strong hydrogen bonds has not been highlighted in detail. Hence a thorough structural investigation is needed to understand the role of "organic fluorine" in crystal engineering of small organic fluorinated molecules having the possibility of strong hydrogen bond formation in the solution and in the solid state. To fulfil this aim, we have synthesized a series of fluorinated amides using 3-methoxyphenylacetic acid and fluorinated anilines and studied their structural properties through single crystal and powder X-ray diffraction methods. Our results indicated that the "organic fluorine" plays a significant role in altering the packing characteristics of the molecule in building specific crystal lattices even in the presence of strong hydrogen bond.

Noncovalent Polymerization of Mesogens Crystallizes Lysozyme: Correlation between Nonamphiphilic Lyotropic Liquid Crystal Phase and Protein Crystal Formation

PubMed Central

Simon, Karen A.; Shetye, Gauri S.; Englich, Ulrich; Wu, Lei; Luk, Yan-Yeung

2011-01-01

Crystallization of proteins is important for fundamental studies and biopharmaceutical development but remains largely an empirical science. Here, we report the use of organic salts that can form a class of unusual non-amphiphilic lyotropic liquid crystals to crystallize the protein lysozyme. Certain non-amphiphilic organic molecules with fused aromatic rings and two charges can assemble into stable thread-like noncovalent polymers that may further form liquid crystal phases in water, traditionally termed chromonic liquid crystals. Using five of these mesogenic molecules as additives to induce protein crystallization, we discover that molecules that can form liquid crystal phases in water are highly effective at inducing the crystal formation of lysozyme, even at concentrations significantly lower than that required for forming liquid crystal phases. This result reveals an example of inducing protein crystallization by the molecular assembly of the additives, and is consistent with a new mechanism by which the strong hydration of an assembly process provides a gradual means to compete for the water molecules to enable solvated proteins to form crystals. PMID:21786812

Heparin-based hydrogels with tunable sulfation & degradation for anti-inflammatory small molecule delivery.

PubMed

Peng, Yifeng; Tellier, Liane E; Temenoff, Johnna S

2016-08-16

Sustained release of anti-inflammatory agents remains challenging for small molecule drugs due to their low molecular weight and hydrophobicity. Therefore, the goal of this study was to control the release of a small molecule anti-inflammatory agent, crystal violet (CV), from hydrogels fabricated with heparin, a highly sulfated glycosaminoglycan capable of binding positively-charged molecules such as CV. In this system, both electrostatic interactions between heparin and CV and hydrogel degradation were tuned simultaneously by varying the level of heparin sulfation and varying the amount of dithiothreitol within hydrogels, respectively. It was found that heparin sulfation significantly affected CV release, whereby more sulfated heparin hydrogels (Hep and Hep(-N)) released CV with near zero-order release kinetics (R-squared values between 0.96-0.99). Furthermore, CV was released more quickly from fast-degrading hydrogels than slow-degrading hydrogels, providing a method to tune total CV release between 5-15 days while maintaining linear release kinetics. In particular, N-desulfated heparin hydrogels exhibited efficient CV loading (∼90% of originally included CV), near zero-order CV release kinetics, and maintenance of CV bioactivity after release, making this hydrogel formulation a promising CV delivery vehicle for a wide range of inflammatory diseases.

“Roller-Wheel”-Type Pt-Containing Small Molecules and the Impact of “Rollers” on Material Crystallinity, Electronic Properties, and Solar Cell Performance

DOE PAGES

He, Wenhan; Livshits, Maksim Y.; Dickie, Diane A.; ...

2017-07-21

We report the synthesis, characterization, and detailed comparison of a series of novel Pt-bisacetylide containing conjugated small molecules possessing an unconventional “roller-wheel” shaped structure that is distinctly different from the “dumbbell” designs in traditional Pt-bisacetylide containing conjugated polymers and small molecules. The relationships between the chemical nature and length of the “rollers” and the electronic and physical properties of the materials are carefully studied by steady-state spectroscopy, cyclic voltammetry, differential scanning calorimetry, single-crystal X-ray diffraction, transient absorption spectroscopy, theoretical calculation, and device application. It was revealed that if the roller are long enough, these molecules can “slip-stack” in the solidmore » state, leading to high crystallinity and charge mobility. Organic solar cells were fabricated and showed power conversion efficiencies up to 5.9%, out-performing all existing Pt-containing materials. The device performance was also found to be sensitive to optimization conditions and blend morphologies, which are a result of the intricate interplay among materials crystallinity, phase separation, and the relative positions of the lowest singlet and triplet excited states.« less

Small-Molecule Modulators of Methyl-Lysine Binding for the CBX7 Chromodomain

DOE PAGES

Ren, Chunyan; Morohashi, Keita; Plotnikov, Alexander N.; ...

2015-02-05

Chromobox homolog 7 (CBX7) plays an important role in gene transcription in a wide array of cellular processes, ranging from stem cell self-renewal and differentiation to tumor progression. CBX7 functions through its N-terminal chromodomain (ChD), which recognizes tri-methylated lysine 27 of histone 3 (H3K27me3), a conserved epigenetic mark that signifies gene transcriptional repression. Here in this study, we report discovery of small molecules that inhibit CBX7ChD binding to H3K27me3. Our crystal structures reveal the binding modes of these molecules that compete against H3K27me3 binding through interactions with key residues in the methyl-lysine binding pocket of CBX7ChD. We further show thatmore » a lead compound MS37452, derepresses transcription of Polycomb repressive complex target gene p16/CDKN2A by displacing CBX7 binding to the INK4A/ARF locus in prostate cancer cells. Ultimately, these small molecules have the potential to be developed into high-potency chemical modulators that target CBX7 functions in gene transcription in different disease pathways.« less

“Roller-Wheel”-Type Pt-Containing Small Molecules and the Impact of “Rollers” on Material Crystallinity, Electronic Properties, and Solar Cell Performance

DOE Office of Scientific and Technical Information (OSTI.GOV)

He, Wenhan; Livshits, Maksim Y.; Dickie, Diane A.

We report the synthesis, characterization, and detailed comparison of a series of novel Pt-bisacetylide containing conjugated small molecules possessing an unconventional “roller-wheel” shaped structure that is distinctly different from the “dumbbell” designs in traditional Pt-bisacetylide containing conjugated polymers and small molecules. The relationships between the chemical nature and length of the “rollers” and the electronic and physical properties of the materials are carefully studied by steady-state spectroscopy, cyclic voltammetry, differential scanning calorimetry, single-crystal X-ray diffraction, transient absorption spectroscopy, theoretical calculation, and device application. It was revealed that if the roller are long enough, these molecules can “slip-stack” in the solidmore » state, leading to high crystallinity and charge mobility. Organic solar cells were fabricated and showed power conversion efficiencies up to 5.9%, out-performing all existing Pt-containing materials. The device performance was also found to be sensitive to optimization conditions and blend morphologies, which are a result of the intricate interplay among materials crystallinity, phase separation, and the relative positions of the lowest singlet and triplet excited states.« less

Recombinant production, crystallization and X-ray crystallographic structure determination of the peptidyl-tRNA hydrolase of Pseudomonas aeruginosa

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hughes, Ronny C.; McFeeters, Hana; Coates, Leighton

The peptidyl-tRNA hydrolase enzyme from the pathogenic bacterium Pseudomonas aeruginosa (Pth; EC 3.1.1.29) has been cloned, expressed in Escherichia coli and crystallized for X-ray structural analysis. Suitable crystals were grown using the sitting-drop vapour-diffusion method after one week of incubation against a reservoir solution consisting of 20% polyethylene glycol 4000, 100 mM Tris pH 7.5, 10%(v/v) isopropyl alcohol. The crystals were used to obtain the three-dimensional structure of the native protein at 1.77 Å resolution. The structure was determined by molecular replacement of the crystallographic data processed in space group P6122 with unit-cell parameters a = b = 63.62,c =more » 155.20 Å, α = β = 90, γ = 120°. The asymmetric unit of the crystallographic lattice was composed of a single copy of the enzyme molecule with a 43% solvent fraction, corresponding to a Matthews coefficient of 2.43 Å3 Da-1. The crystallographic structure reported here will serve as the foundation for future structure-guided efforts towards the development of novel small-molecule inhibitors specific to bacterial Pths.« less

Minimal physical requirements for crystal growth self-poisoning

DOE PAGES

Whitelam, Stephen; Dahal, Yuba Raj; Schmit, Jeremy D.

2016-02-10

Self-poisoning is a kinetic trap that can impair or prevent crystal growth in a wide variety of physical settings. In this paper, we use dynamic mean-field theory and computer simulation to argue that poisoning is ubiquitous because its emergence requires only the notion that a molecule can bind in two (or more) ways to a crystal; that those ways are not energetically equivalent; and that the associated binding events occur with sufficiently unequal probability. If these conditions are met then the steady-state growth rate is in general a non-monotonic function of the thermodynamic driving force for crystal growth, which ismore » the characteristic of poisoning. Finally, our results also indicate that relatively small changes of system parameters could be used to induce recovery from poisoning.« less

Optimization of protein buffer cocktails using Thermofluor.

PubMed

Reinhard, Linda; Mayerhofer, Hubert; Geerlof, Arie; Mueller-Dieckmann, Jochen; Weiss, Manfred S

2013-02-01

The stability and homogeneity of a protein sample is strongly influenced by the composition of the buffer that the protein is in. A quick and easy approach to identify a buffer composition which increases the stability and possibly the conformational homogeneity of a protein sample is the fluorescence-based thermal-shift assay (Thermofluor). Here, a novel 96-condition screen for Thermofluor experiments is presented which consists of buffer and additive parts. The buffer screen comprises 23 different buffers and the additive screen includes small-molecule additives such as salts and nucleotide analogues. The utilization of small-molecule components which increase the thermal stability of a protein sample frequently results in a protein preparation of higher quality and quantity and ultimately also increases the chances of the protein crystallizing.

Synthesis of three new thiophene condensed pyrene derivatives, crystal structure and evaluation of their photophysical properties

NASA Astrophysics Data System (ADS)

Moriguchi, Tetsuji; Yakeya, Daisuke; Tsuge, Akihiko; Jalli, Venkataprasad

2018-04-01

Three new thiophene condensed fluorescent pyrene derivatives have been synthesized by a two-step process, via. Wittig reaction followed by iodine promoted photocyclization. These molecules have been characterized by 1H NMR and EI-MS. Further, the molecular structures of 4a, 4b and 4c has been confirmed by single crystal X-ray diffraction analysis. The protons located in the fjord and cove-regions of molecules 4b and 4c showed downfield shifts of the protons. Molecule 4a crystallized under monoclinic system with space group P21/c, molecule 4b crystallized under monoclinic system with space group C2/c and the molecule 4c crystalized under triclinic system with space group P-1. Molecules 4a, 4b and 4c showed strong absorption maxima wavelengths at 305, 358 and 330 nm, respectively. The molar extinctinction coefficients (ε) of the compounds 4a, 4b and 4c indicated molecule 4c has better ability to absorb UV light, molecule 4b has better fluorescence intensity than molecule 4a and 4c.

Characterization of Crystal Chirality in Amino Acids Using Low-Frequency Raman Spectroscopy.

PubMed

Aviv, Hagit; Nemtsov, Irena; Mastai, Yitzhak; Tischler, Yaakov R

2017-10-19

We present a new method for differentiating racemic crystals from enantiopure crystals. Recently, developments in optical filters have enabled the facile use of Raman spectroscopy to detect low-frequency vibrational (LFV) modes. Here, for the first time, we use Raman spectroscopy to characterize the LFV modes for crystalline organic materials composed of chiral molecules. The LF-Raman spectra of racemic and enantiopure crystals exhibit a significant variation, which we attribute to different hydrogen-bond networks in the chiral crystal structures. Across a representative set of amino acids, we observed that when comparing racemic versus enantiopure crystals, the available LFV modes and their relative scattering intensity are strong functions of side chain polarity. Thus, LF-Raman can be used as a method that is complementary to the currently used methods for characterizing crystal chirality due to simpler, faster, and more sensitive measurements, along with the small sample size required, which is limited by the laser-beam diameter in the focus.

Quality by design in formulation and process development for a freeze-dried, small molecule parenteral product: a case study.

PubMed

Mockus, Linas N; Paul, Timothy W; Pease, Nathan A; Harper, Nancy J; Basu, Prabir K; Oslos, Elizabeth A; Sacha, Gregory A; Kuu, Wei Y; Hardwick, Lisa M; Karty, Jacquelyn J; Pikal, Michael J; Hee, Eun; Khan, Mansoor A; Nail, Steven L

2011-01-01

A case study has been developed to illustrate one way of incorporating a Quality by Design approach into formulation and process development for a small molecule, freeze-dried parenteral product. Sodium ethacrynate was chosen as the model compound. Principal degradation products of sodium ethacrynate result from hydrolysis of the unsaturated ketone in aqueous solution, and dimer formation from a Diels-Alder condensation in the freeze-dried solid state. When the drug crystallizes in a frozen solution, the eutectic melting temperature is above -5°C. Crystallization in the frozen system is affected by pH in the range of pH 6-8 and buffer concentration in the range of 5-50 mM, where higher pH and lower buffer concentration favor crystallization. Physical state of the drug is critical to solid state stability, given the relative instability of amorphous drug. Stability was shown to vary considerably over the ranges of pH and buffer concentration examined, and vial-to-vial variability in degree of crystallinity is a potential concern. The formulation design space was constructed in terms of pH and drug concentration, and assuming a constant 5 mM concentration of buffer. The process design space is constructed to take into account limitations on the process imposed by the product and by equipment capability.

Crystal Engineering; How molecules build solids

NASA Astrophysics Data System (ADS)

Williams, Jeffrey H.

2017-09-01

There are more than 20 million chemicals in the literature, with new materials being synthesized each week. Most of these molecules are stable, and the 3-dimensional arrangement of the atoms in the molecules, in the various solids may be determined by routine x-ray crystallography. When this is done, it is found that this vast range of molecules, with varying sizes and shapes can be accommodated by only a handful of solid structures. This limited number of architectures for the packing of molecules of all shapes and sizes, to maximize attractive intermolecular forces and minimizing repulsive intermolecular forces, allows us to develop simple models of what holds the molecules together in the solid. In this volume we look at the origin of the molecular architecture of crystals; a topic that is becoming increasingly important and is often termed, crystal engineering. Such studies are a means of predicting crystal structures, and of designing crystals with particular properties by manipulating the structure and interaction of large molecules. That is, creating new crystal architectures with desired physical characteristics in which the molecules pack together in particular architectures; a subject of particular interest to the pharmaceutical industry.

High-mobility strained organic semiconductors (Conference Presentation)

NASA Astrophysics Data System (ADS)

Takeya, Jun; Matsui, H.; Kubo, T.; Hausermann, Roger

2016-11-01

Small molecular organic semiconductor crystals form interesting electronic systems of periodically arranged "charge clouds" whose mutual electronic coupling determines whether or not electronic states can be coherent over fluctuating molecules. This presentation focuses on two methods to reduce molecular fluctuation, which strongly restricts mobility of highly mobile charge in single-crystal organic transistors. The first example is to apply external hydrostatic pressure. Using Hall-effect measurement for pentacene FETs, which tells us the extent of the electronic coherence, we found a crossover from hopping-like transport of nearly localized charge to band transport of delocalized charge with full coherence. As the result of temperature dependence measurement, it turned out that reduced molecular fluctuation is mainly responsible for the crossover. The second is to apply uniaxial strain to single-crystal organic FETs. We applied stain by bending thin films of newly synthesized decyldinaphthobenzodithiophene (C10-DNBDT) on plastic substrate so that 3% strain is uniaxially applied. As the result, the room-temperature mobility increased by the factor of 1.7. In-depth analysis using X-ray diffraction (XRD) measurements and density functional theory (DFT) calculations reveal the origin to be the suppression of the thermal fluctuation of the individual molecules, which is confirmed by temperature dependent measurements. Our findings show that compressing the crystal structure directly restricts the vibration of the molecules, thus suppressing dynamic disorder, a unique mechanism in organic semiconductors. Since strain can easily be induced during the fabrication process, these findings can directly be exploited to build high performance organic devices.

Structural Studies on Intact Clostridium botulinum Neurotoxins Complexed with Inhibitors Leading to Drug Design

DTIC Science & Technology

2009-02-01

compounds via virtual screening. These compounds include small molecules – transition state analogues and benzimidazoles . Since there is a commonality in...Crystal structure of BoNT/E has been determined helping us to understand the faster action of BoNT/E compared to BoNT/A. • A subset of benzimidazole

Tunable Wavelength Solid-State Lasers and Turbulent Jet Diagnostics by Rayleigh and Fluorescence Scattering.

DTIC Science & Technology

1981-09-01

5320 radiation with 20 nsec pulse duration. The 12 molecules were introduced into the nozzle gas by placing small pellets of 12 crystals in the gas...ACKNOWLEDENTS We thank R. K. Chang and B. T. Chu for many helpful discussions and Sandia National Laboratories (Livermore) for the loan of the burner

Quantitative analysis of H2O and CO2 in cordierite using polarized FTIR spectroscopy

NASA Astrophysics Data System (ADS)

Della Ventura, Giancarlo; Radica, Francesco; Bellatreccia, Fabio; Cavallo, Andrea; Capitelli, Francesco; Harley, Simon

2012-11-01

We report a FTIR (Fourier transform infrared) study of a set of cordierite samples from different occurrence and with different H2O/CO2 content. The specimens were fully characterized by a combination of techniques including optical microscopy, single-crystal X-ray diffraction, EMPA (electron microprobe analysis), SIMS (secondary ion mass spectrometry), and FTIR spectroscopy. All cordierites are orthorhombic Ccmm. According to the EMPA data, the Si/Al ratio is always close to 5:4; X Mg ranges from 76.31 to 96.63, and additional octahedral constituents occur in very small amounts. Extraframework K and Ca are negligible, while Na reaches the values up to 0.84 apfu. SIMS shows H2O up to 1.52 and CO2 up to 1.11 wt%. Optically transparent single crystals were oriented using the spindle stage and examined by FTIR micro-spectroscopy under polarized light. On the basis of the polarizing behaviour, the observed bands were assigned to water molecules in two different orientations and to CO2 molecules in the structural channels. The IR spectra also show the presence of small amounts of CO in the samples. Refined integrated molar absorption coefficients were calibrated for the quantitative microanalysis of both H2O and CO2 in cordierite based on single-crystal polarized-light FTIR spectroscopy. For H2O the integrated molar coefficients for type I and type II water molecules (ν3 modes) were calculated separately and are [I]ɛ = 5,200 ± 700 l mol-1 cm-2 and [II]ɛ = 13,000 ± 3,000 l mol-1 cm-2, respectively. For CO2 the integrated coefficient is \\varepsilon_{{{{CO}}_{ 2} }} = 19,000 ± 2,000 l mol-1 cm-2.

X-ray crystal structure of plasmin with tranexamic acid-derived active site inhibitors.

PubMed

Law, Ruby H P; Wu, Guojie; Leung, Eleanor W W; Hidaka, Koushi; Quek, Adam J; Caradoc-Davies, Tom T; Jeevarajah, Devadharshini; Conroy, Paul J; Kirby, Nigel M; Norton, Raymond S; Tsuda, Yuko; Whisstock, James C

2017-05-09

The zymogen protease plasminogen and its active form plasmin perform key roles in blood clot dissolution, tissue remodeling, cell migration, and bacterial pathogenesis. Dysregulation of the plasminogen/plasmin system results in life-threatening hemorrhagic disorders or thrombotic vascular occlusion. Accordingly, inhibitors of this system are clinically important. Currently, tranexamic acid (TXA), a molecule that prevents plasminogen activation through blocking recruitment to target substrates, is the most widely used inhibitor for the plasminogen/plasmin system in therapeutics. However, TXA lacks efficacy on the active form of plasmin. Thus, there is a need to develop specific inhibitors that target the protease active site. Here we report the crystal structures of plasmin in complex with the novel YO ( trans -4-aminomethylcyclohexanecarbonyl-l-tyrosine- n -octylamide) class of small molecule inhibitors. We found that these inhibitors form key interactions with the S1 and S3' subsites of the catalytic cleft. Here, the TXA moiety of the YO compounds inserts into the primary (S1) specificity pocket, suggesting that TXA itself may function as a weak plasmin inhibitor, a hypothesis supported by subsequent biochemical and biophysical analyses. Mutational studies reveal that F587 of the S' subsite plays a key role in mediating the inhibitor interaction. Taken together, these data provide a foundation for the future development of small molecule inhibitors to specifically regulate plasmin function in a range of diseases and disorders.

X-ray crystal structure of plasmin with tranexamic acid–derived active site inhibitors

PubMed Central

Wu, Guojie; Leung, Eleanor W. W.; Hidaka, Koushi; Quek, Adam J.; Caradoc-Davies, Tom T.; Jeevarajah, Devadharshini; Kirby, Nigel M.; Norton, Raymond S.; Tsuda, Yuko; Whisstock, James C.

2017-01-01

The zymogen protease plasminogen and its active form plasmin perform key roles in blood clot dissolution, tissue remodeling, cell migration, and bacterial pathogenesis. Dysregulation of the plasminogen/plasmin system results in life-threatening hemorrhagic disorders or thrombotic vascular occlusion. Accordingly, inhibitors of this system are clinically important. Currently, tranexamic acid (TXA), a molecule that prevents plasminogen activation through blocking recruitment to target substrates, is the most widely used inhibitor for the plasminogen/plasmin system in therapeutics. However, TXA lacks efficacy on the active form of plasmin. Thus, there is a need to develop specific inhibitors that target the protease active site. Here we report the crystal structures of plasmin in complex with the novel YO (trans-4-aminomethylcyclohexanecarbonyl-l-tyrosine-n-octylamide) class of small molecule inhibitors. We found that these inhibitors form key interactions with the S1 and S3′ subsites of the catalytic cleft. Here, the TXA moiety of the YO compounds inserts into the primary (S1) specificity pocket, suggesting that TXA itself may function as a weak plasmin inhibitor, a hypothesis supported by subsequent biochemical and biophysical analyses. Mutational studies reveal that F587 of the S′ subsite plays a key role in mediating the inhibitor interaction. Taken together, these data provide a foundation for the future development of small molecule inhibitors to specifically regulate plasmin function in a range of diseases and disorders. PMID:29296720

A small-molecule fragment that emulates binding of receptor and broadly neutralizing antibodies to influenza A hemagglutinin.

PubMed

Kadam, Rameshwar U; Wilson, Ian A

2018-04-17

The influenza virus hemagglutinin (HA) glycoprotein mediates receptor binding and membrane fusion during viral entry in host cells. Blocking these key steps in viral infection has applications for development of novel antiinfluenza therapeutics as well as vaccines. However, the lack of structural information on how small molecules can gain a foothold in the small, shallow receptor-binding site (RBS) has hindered drug design against this important target on the viral pathogen. Here, we report on the serendipitous crystallization-based discovery of a small-molecule N -cyclohexyltaurine, commonly known as the buffering agent CHES, that is able to bind to both group-1 and group-2 HAs of influenza A viruses. X-ray structural characterization of group-1 H5N1 A/Vietnam/1203/2004 (H5/Viet) and group-2 H3N2 A/Hong Kong/1/1968 (H3/HK68) HAs at 2.0-Å and 2.57-Å resolution, respectively, revealed that N -cyclohexyltaurine binds to the heart of the conserved HA RBS. N -cyclohexyltaurine mimics the binding mode of the natural receptor sialic acid and RBS-targeting bnAbs through formation of similar hydrogen bonds and CH-π interactions with the HA. In H3/HK68, N -cyclohexyltaurine also binds to a conserved pocket in the stem region, thereby exhibiting a dual-binding mode in group-2 HAs. These long-awaited structural insights into RBS recognition by a noncarbohydrate-based small molecule enhance our knowledge of how to target this important functional site and can serve as a template to guide the development of novel broad-spectrum small-molecule therapeutics against influenza virus.

Structural basis of AMPK regulation by small molecule activators

NASA Astrophysics Data System (ADS)

Xiao, Bing; Sanders, Matthew J.; Carmena, David; Bright, Nicola J.; Haire, Lesley F.; Underwood, Elizabeth; Patel, Bhakti R.; Heath, Richard B.; Walker, Philip A.; Hallen, Stefan; Giordanetto, Fabrizio; Martin, Stephen R.; Carling, David; Gamblin, Steven J.

2013-12-01

AMP-activated protein kinase (AMPK) plays a major role in regulating cellular energy balance by sensing and responding to increases in AMP/ADP concentration relative to ATP. Binding of AMP causes allosteric activation of the enzyme and binding of either AMP or ADP promotes and maintains the phosphorylation of threonine 172 within the activation loop of the kinase. AMPK has attracted widespread interest as a potential therapeutic target for metabolic diseases including type 2 diabetes and, more recently, cancer. A number of direct AMPK activators have been reported as having beneficial effects in treating metabolic diseases, but there has been no structural basis for activator binding to AMPK. Here we present the crystal structure of human AMPK in complex with a small molecule activator that binds at a site between the kinase domain and the carbohydrate-binding module, stabilising the interaction between these two components. The nature of the activator-binding pocket suggests the involvement of an additional, as yet unidentified, metabolite in the physiological regulation of AMPK. Importantly, the structure offers new opportunities for the design of small molecule activators of AMPK for treatment of metabolic disorders.

Towards the Structure Determination of a Modulated Protein Crystal: The Semicrystalline State of Profilin:Actin

NASA Technical Reports Server (NTRS)

Borgstahl, G.; Lovelace, J.; Snell, E. H.; Bellamy, H.

2003-01-01

One of the remaining challenges to structural biology is the solution of modulated structures. While small molecule crystallographers have championed this type of structure, to date, no modulated macromolecular structures have been determined. Modulation of the molecular structures within the crystal can produce satellite reflections or a superlattice of reflections in reciprocal space. We have developed the data collection methods and strategies that are needed to collect and analyze these data. If the macromolecule's crystal lattice is composed of physiologically relevant packing contacts, structural changes induced under physiological conditions can cause distortion relevant to the function and biophysical processes of the molecule making up the crystal. By careful measurement of the distortion, and the corresponding three-dimensional structure of the distorted molecule, we will visualize the motion and mechanism of the biological macromolecule(s). We have measured the modulated diffraction pattern produced by the semicrystalline state of profilin:actin crystals using highly parallel and highly monochromatic synchrotron radiation coupled with fine phi slicing (0.001-0.010 degrees) for structure determination. These crystals present these crystals present a unique opportunity to address an important question in structural biology. The modulation is believed to be due to the formation of actin helical filaments from the actin beta ribbon upon the pH-induced dissociation of profilin. To date, the filamentous state of actin has resisted crystallization and no detailed structures are available. The semicrystalline state profilin:actin crystals provides a unique opportunity to understand the many conformational states of actin. This knowledge is essential for understanding the dynamics underlying shape changes and motility of eukaryotic cells. Many essential processes, such as cytokinesis, phagocytosis, and cellular migration depend upon the capacity of the actin microfilament system to be restructured in a controlled manner via polymerization, depolymerization, severing, cross-linking, and anchorage. The structure the semicrystalline state of profilin:actin will challenge and validate current models of muscle contraction and cell motility. The methodology and theory under development will be easily extendable to other systems.

Preliminary morphological and X-ray diffraction studies of the crystals of the DNA cetyltrimethylammonium salt.

PubMed

Osica, V D; Pyatigorskaya, T L; Polyvtsev, O F; Dembo, A T; Kliya, M O; Vasilchenko, V N; Verkin, B I; Sukharevskya, B Y

1977-04-01

Double-stranded DNA molecules (molecular weight 2.5 X 10(5) - 5 X 10(5) daltons) have been crystallized from water-salt solutions as cetyltrimethylammonium salts (CTA-DNA). Variation of crystallization conditions results in a production of different types of CTA-DNA crystals: spherulits, dendrites, needle-shaped and faceted rhombic crystals, the latter beeing up to 0.3 mm on a side. X-ray diffraction data indicate that DNA molecules in the crystals form a hexagonal lattice which parameters vary slightly with the morphological type of the crystal. Comparison of the melting curves of the DNA preparation before and after crystallization suggests that DNA molecules are partially fractionated in the course of crystallization. Crystals of the CTA-DNA-proflavine complex have also been obtained.

Preliminary morphological and X-ray diffraction studies of the crystals of the DNA cetyltrimethylammonium salt.

PubMed Central

Osica, V D; Pyatigorskaya, T L; Polyvtsev, O F; Dembo, A T; Kliya, M O; Vasilchenko, V N; Verkin, B I; Sukharevskya, B Y

1977-01-01

Double-stranded DNA molecules (molecular weight 2.5 X 10(5) - 5 X 10(5) daltons) have been crystallized from water-salt solutions as cetyltrimethylammonium salts (CTA-DNA). Variation of crystallization conditions results in a production of different types of CTA-DNA crystals: spherulits, dendrites, needle-shaped and faceted rhombic crystals, the latter beeing up to 0.3 mm on a side. X-ray diffraction data indicate that DNA molecules in the crystals form a hexagonal lattice which parameters vary slightly with the morphological type of the crystal. Comparison of the melting curves of the DNA preparation before and after crystallization suggests that DNA molecules are partially fractionated in the course of crystallization. Crystals of the CTA-DNA-proflavine complex have also been obtained. Images PMID:866188

Single-crystal X-ray diffraction and NMR crystallography of a 1:1 cocrystal of dithianon and pyrimethanil.

PubMed

Pöppler, Ann Christin; Corlett, Emily K; Pearce, Harriet; Seymour, Mark P; Reid, Matthew; Montgomery, Mark G; Brown, Steven P

2017-03-01

A single-crystal X-ray diffraction structure of a 1:1 cocrystal of two fungicides, namely dithianon (DI) and pyrimethanil (PM), is reported [systematic name: 5,10-dioxo-5H,10H-naphtho[2,3-b][1,4]dithiine-2,3-dicarbonitrile-4,6-dimethyl-N-phenylpyrimidin-2-amine (1/1), C 14 H 4 N 2 O 2 S 2 ·C 12 H 13 N 2 ]. Following an NMR crystallography approach, experimental solid-state magic angle spinning (MAS) NMR spectra are presented together with GIPAW (gauge-including projector augmented wave) calculations of NMR chemical shieldings. Specifically, experimental 1 H and 13 C chemical shifts are determined from two-dimensional 1 H- 13 C MAS NMR correlation spectra recorded with short and longer contact times so as to probe one-bond C-H connectivities and longer-range C...H proximities, whereas H...H proximities are identified in a 1 H double-quantum (DQ) MAS NMR spectrum. The performing of separate GIPAW calculations for the full periodic crystal structure and for isolated molecules allows the determination of the change in chemical shift upon going from an isolated molecule to the full crystal structure. For the 1 H NMR chemical shifts, changes of 3.6 and 2.0 ppm correspond to intermolecular N-H...O and C-H...O hydrogen bonding, while changes of -2.7 and -1.5 ppm are due to ring current effects associated with C-H...π interactions. Even though there is a close intermolecular S...O distance of 3.10 Å, it is of note that the molecule-to-crystal chemical shifts for the involved sulfur or oxygen nuclei are small.

Crystallization Physics in Biomacromolecular Systems

NASA Technical Reports Server (NTRS)

Chernov, A. A.

2003-01-01

The crystals are built of molecules of protein, nucleic acid and their complexes, like viruses, approx. 5x10(exp 3)+ 3x10(exp 6) Da in weight and 2 + 20 nm in effective diameter. This size strongly exceeds action range of molecular forces and makes a big difference with inorganic crystals. Intermolecular contacts form patches on the biomacromolecular surface. Each patch may occupy only a small percent of the whole surface and vary from polymorph to polymorph of the same protein. Thus, under different conditions (pH, solution chemistry, temperature, any area on the macromolecular surface may form a contact. The crystal Young moduli, E approx. equals 0.1 + 0.5 GPa are more than 10 times lower than that of inorganics and the biomolecules themselves. Water within biocrystals (30-70%) is unable to flow unless typical deformation time is longer than approx. 10(exp -5)s. This explains the discrepancy between light scattering and static measurements of E. Nucleation and Growth requires typically concentrations exceeding the equilibrium ones up to 100 times - because of the new size scale results in 10 - 10(exp 3) times lower kinetic coefficients than that needed for inorganic solution growth. All phenomena observed in the latter occur with protein crystallization and are even better studied by AFM. Crystals are typically facetted. Among unexpected findings of general significance are - net molecular exchange flux at kinks is much lower than that expected from supersaturation, steps with low (< approx. 10(exp -2)) kink density at steps follow Gibbs-Thomson law only at very low supersaturations, step segment growth rate may be independent of step energy. Crystal perfection is a must of biocrystallization to achieve the major goal to find 3-D atomic structure of biomacromolecules by x-ray diffraction. Poor diffraction resolution (> 3Angstrom) makes crystallization a bottleneck for structural biology. All defects typical of small molecule crystals are found in biocrystals, but the defects responsible for poor resolution are not identified. Conformational changes are one of them. Biocrystallization in microgravity reportedly results in 20% cases of better crystals. The mechanism of how lack of convection can do this is still not clear. Lower supersaturation, self-purification &om preferentially trapped homologous impurities and step bunching are viable hypotheses.

Analytical applications of aptamers

NASA Astrophysics Data System (ADS)

Tombelli, S.; Minunni, M.; Mascini, M.

2007-05-01

Aptamers are single stranded DNA or RNA ligands which can be selected for different targets starting from a library of molecules containing randomly created sequences. Aptamers have been selected to bind very different targets, from proteins to small organic dyes. Aptamers are proposed as alternatives to antibodies as biorecognition elements in analytical devices with ever increasing frequency. This in order to satisfy the demand for quick, cheap, simple and highly reproducible analytical devices, especially for protein detection in the medical field or for the detection of smaller molecules in environmental and food analysis. In our recent experience, DNA and RNA aptamers, specific for three different proteins (Tat, IgE and thrombin), have been exploited as bio-recognition elements to develop specific biosensors (aptasensors). These recognition elements have been coupled to piezoelectric quartz crystals and surface plasmon resonance (SPR) devices as transducers where the aptamers have been immobilized on the gold surface of the crystals electrodes or on SPR chips, respectively.

A Supramolecular Ice Growth Inhibitor.

PubMed

Drori, Ran; Li, Chao; Hu, Chunhua; Raiteri, Paolo; Rohl, Andrew L; Ward, Michael D; Kahr, Bart

2016-10-12

Safranine O, a synthetic dye, was found to inhibit growth of ice at millimolar concentrations with an activity comparable to that of highly evolved antifreeze glycoproteins. Safranine inhibits growth of ice crystals along the crystallographic a-axis, resulting in bipyramidal needles extended along the <0001> directions as well as and plane-specific thermal hysteresis (TH) activity. The interaction of safranine with ice is reversible, distinct from the previously reported behavior of antifreeze proteins. Spectroscopy and molecular dynamics indicate that safranine forms aggregates in aqueous solution at micromolar concentrations. Metadynamics simulations and aggregation theory suggested that as many as 30 safranine molecules were preorganized in stacks at the concentrations where ice growth inhibition was observed. The simulations and single-crystal X-ray structure of safranine revealed regularly spaced amino and methyl substituents in the aggregates, akin to the ice-binding site of antifreeze proteins. Collectively, these observations suggest an unusual link between supramolecular assemblies of small molecules and functional proteins.

The Curious Case of 2-Propyl-1H-benzimidazole in the Solid State: An Experimental and Theoretical Study.

PubMed

Quesada-Moreno, María Mar; Cruz-Cabeza, Aurora J; Avilés-Moreno, Juan Ramón; Cabildo, Pilar; Claramunt, Rosa M; Alkorta, Ibon; Elguero, José; Zúñiga, Francisco J; López-González, Juan Jesús

2017-08-03

2-Propyl-1H-benzimidazole (2PrBzIm) is a small molecule, commercially available, which displays a curious behavior in the solid state. 2PrBzIm, although devoid of chirality by fast rotation about a single bond of the propyl group in solution, crystallizes as a conglomerate showing chiroptical properties. An exhaustive analysis of its crystal structure and a wide range of experiments monitored by vibrational circular dichroism spectroscopy eliminated all possibilities of an artifact. What remains is a new example of the unexplained phenomenon of persistent supramolecular chirality.

Thermally programmable gas storage and release in single crystals of an organic van der Waals host.

PubMed

Enright, Gary D; Udachin, Konstantin A; Moudrakovski, Igor L; Ripmeester, John A

2003-08-20

A single crystal of a low density form of guest-free p-tert-butylcalix[4]arene can take up and release small guest molecules by controlling the temperature and pressure without changing the structure. Using NMR spectroscopy with flowing hyperpolarized xenon, we have shown that at room temperature access of xenon to the pore system is difficult, whereas it is relatively easy at 100 degrees C. There are good prospects for simple van der Waals materials such as the title material to be used as programmable zeolite mimics.

Identification of Small Molecules against Botulinum Neurotoxin B Binding to Neuronal Cells at Ganglioside GT1b Binding Site with Low to Moderate Affinity

DTIC Science & Technology

2014-10-01

BoNT serotype B (BoNT/B) for the trisaccharide GT1b were identified from the x-ray crystal structure of the BoNT/B/trisaccharide (GT1b) complex ( PDB ...trisaccharide and all the water from the structure and identified four potential binding pockets (Pocket-1, Pocket-2, and Pocket-4) as shown in...four potential binding sites or pockets on BoNT serotype B (BoNT/B) for the trisaccharide GT1b were identified from the x-ray crystal structure of the

Crystal structure of phosphoethanolamine methyltransferase from Plasmodium falciparum in complex with amodiaquine

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Soon Goo; Alpert, Tara D.; Jez, Joseph M.

2012-07-17

Phosphoethanolamine N-methyltransferase (PMT) is essential for phospholipid biogenesis in the malarial parasite Plasmodium falciparum. PfPMT catalyzes the triple methylation of phosphoethanolamine to produce phosphocholine, which is then used for phosphatidylcholine synthesis. Here we describe the 2.0 {angstrom} resolution X-ray crystal structure of PfPMT in complex with amodiaquine. To better characterize inhibition of PfPMT by amodiaquine, we determined the IC{sub 50} values of a series of aminoquinolines using a direct radiochemical assay. Both structural and functional analyses provide a possible approach for the development of new small molecule inhibitors of PfPMT.

Mass sensor based on split-nanobeam optomechanical oscillator

NASA Astrophysics Data System (ADS)

Zhang, Yeping; Ai, Jie; Xiang, Yanjun; He, Qinghua; Li, Tao; Ma, Jingfang

2016-03-01

Mass sensing based on monitoring the frequency shifts induced by added mass in oscillators is a well-known and widely used technique. The optomechanical crystal cavity has strong interaction between optical mode and mechanical mode. Radiation pressure driven optomechanical crystal cavity are excellent candidates for mass detection due to their simplicity, sensitivity and all optical operation. In an optomechanical crystal cavity, a high quality factor optical mode simultaneously serves as an efficient actuator and a sensitive probe for precise monitoring the mechanical frequency change of the cavity structure. Here, a split-nanobeam optomechanical crystal cavity is proposed, the sensing resolution as small as 0.33ag (1ag=10-21kg) and the frequency shift is more than 30MHz. This is important and promising for achieve ultimate-precision mass sensing including proteins and other molecules.

Liquid crystal templating as an approach to spatially and temporally organise soft matter.

PubMed

van der Asdonk, Pim; Kouwer, Paul H J

2017-10-02

Chemistry quickly moves from a molecular science to a systems science. This requires spatial and temporal control over the organisation of molecules and molecular assemblies. Whilst Nature almost by default (transiently) organises her components at multiple different length scales, scientists struggle to realise even relatively straightforward patterns. In the past decades, supramolecular chemistry has taught us the rules to precisely engineer molecular assembly at the nanometre scale. At higher length scales, however, we are bound to top-down nanotechnology techniques to realise order. For soft, biological matter, many of these top-down techniques come with serious limitations since the molecules generally show low susceptibilities to the applied stimuli. A new method is based on liquid crystal templating. In this hierarchical approach, a liquid crystalline host serves as the scaffold to order polymers or assemblies. Being a liquid crystal, the host material can be ordered at many different length scales and on top of that, is highly susceptible to many external stimuli, which can even be used to manipulate the liquid crystal organisation in time. As a result, we anticipate large control over the organisation of the materials inside the liquid crystalline host. Recently, liquid crystal templating was also realised in water. This suddenly makes this tool highly applicable to start organising more delicate biological materials or even small organisms. We review the scope and limitations of liquid crystal templating and look out to where the technique may lead us.

Discovering H-bonding rules in crystals with inductive logic programming.

PubMed

Ando, Howard Y; Dehaspe, Luc; Luyten, Walter; Van Craenenbroeck, Elke; Vandecasteele, Henk; Van Meervelt, Luc

2006-01-01

In the domain of crystal engineering, various schemes have been proposed for the classification of hydrogen bonding (H-bonding) patterns observed in 3D crystal structures. In this study, the aim is to complement these schemes with rules that predict H-bonding in crystals from 2D structural information only. Modern computational power and the advances in inductive logic programming (ILP) can now provide computational chemistry with the opportunity for extracting structure-specific rules from large databases that can be incorporated into expert systems. ILP technology is here applied to H-bonding in crystals to develop a self-extracting expert system utilizing data in the Cambridge Structural Database of small molecule crystal structures. A clear increase in performance was observed when the ILP system DMax was allowed to refer to the local structural environment of the possible H-bond donor/acceptor pairs. This ability distinguishes ILP from more traditional approaches that build rules on the basis of global molecular properties.

Effect of bromine deficiency on the lattice dynamics and dielectric properties of alpha-phase diisopropylammonium bromide molecular crystals

NASA Astrophysics Data System (ADS)

Alsaad, Ahmad; Marin, Chris M.; Alaqtash, Nabil; Chao, Hsien-Wen; Chang, Tsun-Hsu; Cheung, Chin Li; Ahmad, A.; Qattan, I. A.; Sabirianov, Renat F.

2018-02-01

Diisopropylammonium bromide (DIPAB) molecular ferroelectric crystals were synthesized and examined to exhibit a large electric polarization (∼23μC/cm2), a large dielectric constant in the α-phase. Although the PXRD pattern indicates that the α-DIPAB sample has an overall excellent crystallinity, our analysis of its FT-IR and Raman vibrational spectra suggests the presence of disorder in the synthesized crystals as indicated by the presence of broad features in the Raman spectrum. Using vdW+DF2 calculations, we identified the majority of vibrational modes in the experimental spectra and analyzed the ones due to Br-disorder. We found that the bromine (Br) deficiency strongly affects the electric properties of α-DIPAB. Particularly, the experimentally measured dielectric constant of α-DIPAB is large (∼20), whereas the DFT-based calculations of the ideal DIPAB give much smaller values (∼2-3). We find that Br-deficiency is responsible for large dielectric constant of the DIPAB crystal with calculated value of ∼15-20. Furthermore, we showed that the van der Waals forces have a slight effect on the structural parameters, only causing a small shift in the vibrational frequencies. The main vibrational features of the DIPAB crystal in the Raman spectrum were shown to be driven by covalent bonding in the DIPA molecules and hydrogen bonds between the molecules with Br.

Hyperoxaluria Requires TNF Receptors to Initiate Crystal Adhesion and Kidney Stone Disease.

PubMed

Mulay, Shrikant R; Eberhard, Jonathan N; Desai, Jyaysi; Marschner, Julian A; Kumar, Santhosh V R; Weidenbusch, Marc; Grigorescu, Melissa; Lech, Maciej; Eltrich, Nuru; Müller, Lisa; Hans, Wolfgang; Hrabě de Angelis, Martin; Vielhauer, Volker; Hoppe, Bernd; Asplin, John; Burzlaff, Nicolai; Herrmann, Martin; Evan, Andrew; Anders, Hans-Joachim

2017-03-01

Intrarenal crystals trigger inflammation and renal cell necroptosis, processes that involve TNF receptor (TNFR) signaling. Here, we tested the hypothesis that TNFRs also have a direct role in tubular crystal deposition and progression of hyperoxaluria-related CKD. Immunohistochemical analysis revealed upregulated tubular expression of TNFR1 and TNFR2 in human and murine kidneys with calcium oxalate (CaOx) nephrocalcinosis-related CKD compared with controls. Western blot and mRNA expression analyses in mice yielded consistent data. When fed an oxalate-rich diet, wild-type mice developed progressive CKD, whereas Tnfr1-, Tnfr2- , and Tnfr1/2- deficient mice did not. Despite identical levels of hyperoxaluria, Tnfr1-, Tnfr2- , and Tnfr1/2 -deficient mice also lacked the intrarenal CaOx deposition and tubular damage observed in wild-type mice. Inhibition of TNFR signaling prevented the induced expression of the crystal adhesion molecules, CD44 and annexin II, in tubular epithelial cells in vitro and in vivo , and treatment with the small molecule TNFR inhibitor R-7050 partially protected hyperoxaluric mice from nephrocalcinosis and CKD. We conclude that TNFR signaling is essential for CaOx crystal adhesion to the luminal membrane of renal tubules as a fundamental initiating mechanism of oxalate nephropathy. Furthermore, therapeutic blockade of TNFR might delay progressive forms of nephrocalcinosis in oxalate nephropathy, such as primary hyperoxaluria. Copyright © 2017 by the American Society of Nephrology.

Hyperoxaluria Requires TNF Receptors to Initiate Crystal Adhesion and Kidney Stone Disease

PubMed Central

Mulay, Shrikant R.; Eberhard, Jonathan N.; Desai, Jyaysi; Marschner, Julian A.; Kumar, Santhosh V.R.; Weidenbusch, Marc; Grigorescu, Melissa; Lech, Maciej; Eltrich, Nuru; Müller, Lisa; Hans, Wolfgang; Hrabě de Angelis, Martin; Vielhauer, Volker; Hoppe, Bernd; Asplin, John; Burzlaff, Nicolai; Herrmann, Martin; Evan, Andrew

2017-01-01

Intrarenal crystals trigger inflammation and renal cell necroptosis, processes that involve TNF receptor (TNFR) signaling. Here, we tested the hypothesis that TNFRs also have a direct role in tubular crystal deposition and progression of hyperoxaluria-related CKD. Immunohistochemical analysis revealed upregulated tubular expression of TNFR1 and TNFR2 in human and murine kidneys with calcium oxalate (CaOx) nephrocalcinosis-related CKD compared with controls. Western blot and mRNA expression analyses in mice yielded consistent data. When fed an oxalate-rich diet, wild-type mice developed progressive CKD, whereas Tnfr1-, Tnfr2-, and Tnfr1/2-deficient mice did not. Despite identical levels of hyperoxaluria, Tnfr1-, Tnfr2-, and Tnfr1/2-deficient mice also lacked the intrarenal CaOx deposition and tubular damage observed in wild-type mice. Inhibition of TNFR signaling prevented the induced expression of the crystal adhesion molecules, CD44 and annexin II, in tubular epithelial cells in vitro and in vivo, and treatment with the small molecule TNFR inhibitor R-7050 partially protected hyperoxaluric mice from nephrocalcinosis and CKD. We conclude that TNFR signaling is essential for CaOx crystal adhesion to the luminal membrane of renal tubules as a fundamental initiating mechanism of oxalate nephropathy. Furthermore, therapeutic blockade of TNFR might delay progressive forms of nephrocalcinosis in oxalate nephropathy, such as primary hyperoxaluria. PMID:27612997

ESR and X-ray Structure Investigations on the Binding and Mechanism of Inhibition of the Native State of Myeloperoxidase with Low Molecular Weight Fragments

DOE PAGES

Chavali, Balagopalakrishna; Masquelin, Thierry; Nilges, Mark J.; ...

2015-05-19

As an early visitor to the injured loci, neutrophil-derived human Myeloperoxidase (hMPO) offers an attractive protein target to modulate the inflammation of the host tissue through suitable inhibitors. We describe a novel methodology of using low temperature ESR spectroscopy (6 K) and FAST™ technology to screen a diverse series of small molecules that inhibit the peroxidase function through reversible binding to the native state of MPO. Also, our initial efforts to profile molecules on the inhibition of MPO-initiated nitration of the Apo-A1 peptide (AEYHAKATEHL) assay showed several potent (with sub-micro molar IC50s) but spurious inhibitors that either do not bindmore » to the heme pocket in the enzyme or retain high (>50 %) anti oxidant potential. Such molecules when taken forward for X-ray did not yield inhibitor-bound co-crystals. We then used ESR to confirm direct binding to the native state enzyme, by measuring the binding-induced shift in the electronic parameter g to rank order the molecules. Molecules with a higher rank order—those with g-shift R relative ≥15—yielded well-formed protein-bound crystals (n = 33 structures). The co-crystal structure with the LSN217331 inhibitor reveals that the chlorophenyl group projects away from the heme along the edges of the Phe366 and Phe407 side chain phenyl rings thereby sterically restricting the access to the heme by the substrates like H 2O 2. Both ESR and antioxidant screens were used to derive the mechanism of action (reversibility, competitive substrate inhibition, and percent antioxidant potential). In conclusion, our results point to a viable path forward to target the native state of MPO to tame local inflammation.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chavali, Balagopalakrishna; Masquelin, Thierry; Nilges, Mark J.

As an early visitor to the injured loci, neutrophil-derived human Myeloperoxidase (hMPO) offers an attractive protein target to modulate the inflammation of the host tissue through suitable inhibitors. We describe a novel methodology of using low temperature ESR spectroscopy (6 K) and FAST™ technology to screen a diverse series of small molecules that inhibit the peroxidase function through reversible binding to the native state of MPO. Also, our initial efforts to profile molecules on the inhibition of MPO-initiated nitration of the Apo-A1 peptide (AEYHAKATEHL) assay showed several potent (with sub-micro molar IC50s) but spurious inhibitors that either do not bindmore » to the heme pocket in the enzyme or retain high (>50 %) anti oxidant potential. Such molecules when taken forward for X-ray did not yield inhibitor-bound co-crystals. We then used ESR to confirm direct binding to the native state enzyme, by measuring the binding-induced shift in the electronic parameter g to rank order the molecules. Molecules with a higher rank order—those with g-shift R relative ≥15—yielded well-formed protein-bound crystals (n = 33 structures). The co-crystal structure with the LSN217331 inhibitor reveals that the chlorophenyl group projects away from the heme along the edges of the Phe366 and Phe407 side chain phenyl rings thereby sterically restricting the access to the heme by the substrates like H 2O 2. Both ESR and antioxidant screens were used to derive the mechanism of action (reversibility, competitive substrate inhibition, and percent antioxidant potential). In conclusion, our results point to a viable path forward to target the native state of MPO to tame local inflammation.« less

In silico screening for Plasmodium falciparum enoyl-ACP reductase inhibitors

NASA Astrophysics Data System (ADS)

Lindert, Steffen; Tallorin, Lorillee; Nguyen, Quynh G.; Burkart, Michael D.; McCammon, J. Andrew

2015-01-01

The need for novel therapeutics against Plasmodium falciparum is urgent due to recent emergence of multi-drug resistant malaria parasites. Since fatty acids are essential for both the liver and blood stages of the malarial parasite, targeting fatty acid biosynthesis is a promising strategy for combatting P. falciparum. We present a combined computational and experimental study to identify novel inhibitors of enoyl-acyl carrier protein reductase ( PfENR) in the fatty acid biosynthesis pathway. A small-molecule database from ChemBridge was docked into three distinct PfENR crystal structures that provide multiple receptor conformations. Two different docking algorithms were used to generate a consensus score in order to rank possible small molecule hits. Our studies led to the identification of five low-micromolar pyrimidine dione inhibitors of PfENR.

Microgravity

NASA Image and Video Library

2004-04-15

The loss of productivity due to flu is staggering. Costs range as much as $20 billio a year. High mutation rates of the flu virus have hindered development of new drugs or vaccines. The secret lies in a small molecule which is attached to the host cell's surface. Each flu virus, no matter what strain, must remove this small molecule to escape the host cell to spread infection. Using data from space and earth grown crystals, researchers from the Center of Macromolecular Crystallography (CMC) are desining drugs to bind with this protein's active site. This lock and key fit reduces the spread of flu in the body by blocking its escape route. In collaboration with its corporate partner, the CMC has refined drug structure in preparation for clinical trials. Tested and approved relief is expected to reach drugstores by year 2004.

Targeting Mycobacterium tuberculosis nucleoid-associated protein HU with structure-based inhibitors

NASA Astrophysics Data System (ADS)

Bhowmick, Tuhin; Ghosh, Soumitra; Dixit, Karuna; Ganesan, Varsha; Ramagopal, Udupi A.; Dey, Debayan; Sarma, Siddhartha P.; Ramakumar, Suryanarayanarao; Nagaraja, Valakunja

2014-06-01

The nucleoid-associated protein HU plays an important role in maintenance of chromosomal architecture and in global regulation of DNA transactions in bacteria. Although HU is essential for growth in Mycobacterium tuberculosis (Mtb), there have been no reported attempts to perturb HU function with small molecules. Here we report the crystal structure of the N-terminal domain of HU from Mtb. We identify a core region within the HU-DNA interface that can be targeted using stilbene derivatives. These small molecules specifically inhibit HU-DNA binding, disrupt nucleoid architecture and reduce Mtb growth. The stilbene inhibitors induce gene expression changes in Mtb that resemble those induced by HU deficiency. Our results indicate that HU is a potential target for the development of therapies against tuberculosis.

Role of Crystallization in the Morphology of Polymer: Non-fullerene Acceptor Bulk Heterojunctions

DOE PAGES

O’Hara, Kathryn A.; Ostrowski, David P.; Koldemir, Unsal; ...

2017-05-22

Many high efficiency organic photovoltaics use fullerene-based acceptors despite their high production cost, weak optical absorption in the visible range, and limited synthetic variability of electronic and optical properties. To circumvent this deficiency, non-fullerene small-molecule acceptors have been developed that have good synthetic flexibility, allowing for precise tuning of optoelectronic properties, leading to enhanced absorption of the solar spectrum and increased open-circuit voltages ( V OC). We examined the detailed morphology of bulk heterojunctions of poly(3-hexylthiophene) and the small-molecule acceptor HPI-BT to reveal structural changes that lead to improvements in the fill factor of solar cells upon thermal annealing. Themore » kinetics of the phase transformation process of HPI-BT during thermal annealing were investigated through in situ grazing incidence wide-angle X-ray scattering studies, atomic force microscopy, and transmission electron microscopy. The HPI-BT acceptor crystallizes during film formation to form micron-sized domains embedded within the film center and a donor rich capping layer at the cathode interface reducing efficient charge extraction. Thermal annealing changes the surface composition and improves charge extraction. In conclusion, this study reveals the need for complementary methods to investigate the morphology of BHJs.« less

Role of Crystallization in the Morphology of Polymer: Non-fullerene Acceptor Bulk Heterojunctions

DOE Office of Scientific and Technical Information (OSTI.GOV)

O’Hara, Kathryn A.; Ostrowski, David P.; Koldemir, Unsal

Many high efficiency organic photovoltaics use fullerene-based acceptors despite their high production cost, weak optical absorption in the visible range, and limited synthetic variability of electronic and optical properties. To circumvent this deficiency, non-fullerene small-molecule acceptors have been developed that have good synthetic flexibility, allowing for precise tuning of optoelectronic properties, leading to enhanced absorption of the solar spectrum and increased open-circuit voltages ( V OC). We examined the detailed morphology of bulk heterojunctions of poly(3-hexylthiophene) and the small-molecule acceptor HPI-BT to reveal structural changes that lead to improvements in the fill factor of solar cells upon thermal annealing. Themore » kinetics of the phase transformation process of HPI-BT during thermal annealing were investigated through in situ grazing incidence wide-angle X-ray scattering studies, atomic force microscopy, and transmission electron microscopy. The HPI-BT acceptor crystallizes during film formation to form micron-sized domains embedded within the film center and a donor rich capping layer at the cathode interface reducing efficient charge extraction. Thermal annealing changes the surface composition and improves charge extraction. In conclusion, this study reveals the need for complementary methods to investigate the morphology of BHJs.« less

Identification of DNA primase inhibitors via a combined fragment-based and virtual screening

NASA Astrophysics Data System (ADS)

Ilic, Stefan; Akabayov, Sabine R.; Arthanari, Haribabu; Wagner, Gerhard; Richardson, Charles C.; Akabayov, Barak

2016-11-01

The structural differences between bacterial and human primases render the former an excellent target for drug design. Here we describe a technique for selecting small molecule inhibitors of the activity of T7 DNA primase, an ideal model for bacterial primases due to their common structural and functional features. Using NMR screening, fragment molecules that bind T7 primase were identified and then exploited in virtual filtration to select larger molecules from the ZINC database. The molecules were docked to the primase active site using the available primase crystal structure and ranked based on their predicted binding energies to identify the best candidates for functional and structural investigations. Biochemical assays revealed that some of the molecules inhibit T7 primase-dependent DNA replication. The binding mechanism was delineated via NMR spectroscopy. Our approach, which combines fragment based and virtual screening, is rapid and cost effective and can be applied to other targets.

Hydration of nucleic acid fragments: comparison of theory and experiment for high-resolution crystal structures of RNA, DNA, and DNA-drug complexes.

PubMed Central

Hummer, G; García, A E; Soumpasis, D M

1995-01-01

A computationally efficient method to describe the organization of water around solvated biomolecules is presented. It is based on a statistical mechanical expression for the water-density distribution in terms of particle correlation functions. The method is applied to analyze the hydration of small nucleic acid molecules in the crystal environment, for which high-resolution x-ray crystal structures have been reported. Results for RNA [r(ApU).r(ApU)] and DNA [d(CpG).d(CpG) in Z form and with parallel strand orientation] and for DNA-drug complexes [d(CpG).d(CpG) with the drug proflavine intercalated] are described. A detailed comparison of theoretical and experimental data shows positional agreement for the experimentally observed water sites. The presented method can be used for refinement of the water structure in x-ray crystallography, hydration analysis of nuclear magnetic resonance structures, and theoretical modeling of biological macromolecules such as molecular docking studies. The speed of the computations allows hydration analyses of molecules of almost arbitrary size (tRNA, protein-nucleic acid complexes, etc.) in the crystal environment and in aqueous solution. Images FIGURE 1 FIGURE 2 FIGURE 5 FIGURE 6 FIGURE 9 FIGURE 12 FIGURE 13 PMID:7542034

Recent Advances in Biosensing With Photonic Crystal Surfaces: A Review

PubMed Central

Cunningham, B.T.; Zhang, M.; Zhuo, Y.; Kwon, L.; Race, C.

2016-01-01

Photonic crystal surfaces that are designed to function as wavelength-selective optical resonators have become a widely adopted platform for label-free biosensing, and for enhancement of the output of photon-emitting tags used throughout life science research and in vitro diagnostics. While some applications, such as analysis of drug-protein interactions, require extremely high resolution and the ability to accurately correct for measurement artifacts, others require sensitivity that is high enough for detection of disease biomarkers in serum with concentrations less than 1 pg/ml. As the analysis of cells becomes increasingly important for studying the behavior of stem cells, cancer cells, and biofilms under a variety of conditions, approaches that enable high resolution imaging of live cells without cytotoxic stains or photobleachable fluorescent dyes are providing new tools to biologists who seek to observe individual cells over extended time periods. This paper will review several recent advances in photonic crystal biosensor detection instrumentation and device structures that are being applied towards direct detection of small molecules in the context of high throughput drug screening, photonic crystal fluorescence enhancement as utilized for high sensitivity multiplexed cancer biomarker detection, and label-free high resolution imaging of cells and individual nanoparticles as a new tool for life science research and single-molecule diagnostics. PMID:27642265

Sizing of colloidal particle and protein molecules in a hanging fluid drop

NASA Technical Reports Server (NTRS)

Ansari, Rafat R.; Suh, Kwang I.

1995-01-01

We report non-invasive particle size measurements of polystyrene latex colloidal particles and bovine serum albumin (BSA) protein molecules suspended in tiny hanging fluid drops of 30 micro-Liter volume using a newly designed fiber optic probe. The probe is based upon the principles of the technique of dynamic light scattering (DLS). The motivation for this work comes from growing protein crystals in outer space. Protein crystals have been grown previously in hanging drops in microgravity experiments on-board the space shuttle orbiter. However, obtaining quantitative information on nucleation and growth of the protein crystals in real time has always been a desired goal, but hitherto not achieved. Several protein researchers have shown interest in using DLS to monitor crystal growth process in a droplet, but elaborate instrumentation and optical alignment problems have made in-situ applications difficult. We demonstrate that such an experiment is now possible. Our system offers fast (5 seconds) determination of particle size, utilize safe levels of very low laser power (less than or equal to 0.2 mW), a small scattering volume (approximately 2 x 10(exp -5) cu mm) and high spatial coherence (Beta) values. This is a major step forward when compared to currently available DLS systems.

Synthesis and Structural Features of [4,4'-Diisopropoxyester-2,2'-bipyridine], [Dichloro(4,4'-diisopropoxyester-2,2'-bi-pyridine)-platinum(ii)] and Its Dichloromethane Solvated Pseudo-Polymorph: Versatile Supramolecular Interactions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Browning, Charles; Nesterov, Vladimir N.; Wang, Xiaoping

We report that the organic ligand 4,4'-diisopropoxyester-2,2'-bipyridine, C 18H 20N 2O 4 (1), crystallizes in the triclinic crystal system P-1 and the molecule occupies a special position in the unit cell. In the crystal, molecules form stacks with partial overlapping of the pyridine rings. The Pt(II) dichloro complex of 1 crystallizes from a mixture of ethanol/hexane and from dichloromethane to form orange and yellow crystals, respectively. The orange non-solvated crystals of the (bipyridine)(dichloro)platinum(II) complex C 18H 20N 2O 4PtCl 2 (2) crystallize in the triclinic crystal system P-1 as well with two independent molecules in the unit cell. In themore » crystal packing, molecules form two types of dimers with Pt1 ··· Pt1A and Pt2···Pt2A distances of 3.478 and 5.186 angstrom respectively. The yellow crystals, as a solvated pseudo-polymorph C 18H 20N 2O 4PtCl 2·1.5 CH 2Cl 2 (3) also crystallize in the triclinic crystal system P-1 with two independent molecules in the unit cell. In the crystal packing, molecules form Pt2 ···Pt1 ···Pt1A ···Pt2A intermolecular contacts with alternating distances 3.501 and 3.431 angstrom, respectively, forming infinite chains. Graphical Abstract The dichloro(bipyridine)platinum complex, dichloro(4,4'-diisopropoxyester-2,2'-bipyridine)platinum(II), forms single crystals as a stable non-solvated form and a solvated polymorph with dramatically different supramolecular structure and short contacts.« less

Synthesis and Structural Features of [4,4'-Diisopropoxyester-2,2'-bipyridine], [Dichloro(4,4'-diisopropoxyester-2,2'-bi-pyridine)-platinum(ii)] and Its Dichloromethane Solvated Pseudo-Polymorph: Versatile Supramolecular Interactions

DOE PAGES

Browning, Charles; Nesterov, Vladimir N.; Wang, Xiaoping; ...

2015-06-03

We report that the organic ligand 4,4'-diisopropoxyester-2,2'-bipyridine, C 18H 20N 2O 4 (1), crystallizes in the triclinic crystal system P-1 and the molecule occupies a special position in the unit cell. In the crystal, molecules form stacks with partial overlapping of the pyridine rings. The Pt(II) dichloro complex of 1 crystallizes from a mixture of ethanol/hexane and from dichloromethane to form orange and yellow crystals, respectively. The orange non-solvated crystals of the (bipyridine)(dichloro)platinum(II) complex C 18H 20N 2O 4PtCl 2 (2) crystallize in the triclinic crystal system P-1 as well with two independent molecules in the unit cell. In themore » crystal packing, molecules form two types of dimers with Pt1 ··· Pt1A and Pt2···Pt2A distances of 3.478 and 5.186 angstrom respectively. The yellow crystals, as a solvated pseudo-polymorph C 18H 20N 2O 4PtCl 2·1.5 CH 2Cl 2 (3) also crystallize in the triclinic crystal system P-1 with two independent molecules in the unit cell. In the crystal packing, molecules form Pt2 ···Pt1 ···Pt1A ···Pt2A intermolecular contacts with alternating distances 3.501 and 3.431 angstrom, respectively, forming infinite chains. Graphical Abstract The dichloro(bipyridine)platinum complex, dichloro(4,4'-diisopropoxyester-2,2'-bipyridine)platinum(II), forms single crystals as a stable non-solvated form and a solvated polymorph with dramatically different supramolecular structure and short contacts.« less

Discovery of GPX4 inhibitory peptides from random peptide T7 phage display and subsequent structural analysis.

PubMed

Sakamoto, Kotaro; Sogabe, Satoshi; Kamada, Yusuke; Matsumoto, Shin-Ichi; Kadotani, Akito; Sakamoto, Jun-Ichi; Tani, Akiyoshi

2017-01-08

The phospholipid hydroperoxidase glutathione peroxidase (GPX4) is an enzyme that reduces lipid hydroperoxides in lipid membranes. Recently, GPX4 has been investigated as a target molecule that induces iron-dependent cell death (ferroptosis) selectively in cancer cells that express mutant Ras. GPX4 inhibitors have the potential to become novel anti-cancer drugs. However, there are no druggable pockets for conventional small molecules on the molecular surface of GPX4. To generate GPX4 inhibitors, we examined the use of peptides as an alternative to small molecules. By screening peptide libraries displayed on T7 phages, and analyzing the X-ray crystal structures of the peptides, we successfully identified one peptide that binds to near Sec73 of catalytic site and two peptides that bind to another site on GPX4. To our knowledge, this is the first study reporting GPX4 inhibitory peptides and their structural information. Copyright © 2016 Elsevier Inc. All rights reserved.

Neutron Nucleic Acid Crystallography.

PubMed

Chatake, Toshiyuki

2016-01-01

The hydration shells surrounding nucleic acids and hydrogen-bonding networks involving water molecules and nucleic acids are essential interactions for the structural stability and function of nucleic acids. Water molecules in the hydration shells influence various conformations of DNA and RNA by specific hydrogen-bonding networks, which often contribute to the chemical reactivity and molecular recognition of nucleic acids. However, X-ray crystallography could not provide a complete description of structural information with respect to hydrogen bonds. Indeed, X-ray crystallography is a powerful tool for determining the locations of water molecules, i.e., the location of the oxygen atom of H2O; however, it is very difficult to determine the orientation of the water molecules, i.e., the orientation of the two hydrogen atoms of H2O, because X-ray scattering from the hydrogen atom is very small.Neutron crystallography is a specialized tool for determining the positions of hydrogen atoms. Neutrons are not diffracted by electrons, but are diffracted by atomic nuclei; accordingly, neutron scattering lengths of hydrogen and its isotopes are comparable to those of non-hydrogen atoms. Therefore, neutron crystallography can determine both of the locations and orientations of water molecules. This chapter describes the current status of neutron nucleic acid crystallographic research as well as the basic principles of neutron diffraction experiments performed on nucleic acid crystals: materials, crystallization, diffraction experiments, and structure determination.

Computational Design of Ligand Binding Proteins with High Affinity and Selectivity

PubMed Central

Dou, Jiayi; Doyle, Lindsey; Nelson, Jorgen W.; Schena, Alberto; Jankowski, Wojciech; Kalodimos, Charalampos G.; Johnsson, Kai; Stoddard, Barry L.; Baker, David

2014-01-01

The ability to design proteins with high affinity and selectivity for any given small molecule would have numerous applications in biosensing, diagnostics, and therapeutics, and is a rigorous test of our understanding of the physiochemical principles that govern molecular recognition phenomena. Attempts to design ligand binding proteins have met with little success, however, and the computational design of precise molecular recognition between proteins and small molecules remains an “unsolved problem”1. We describe a general method for the computational design of small molecule binding sites with pre-organized hydrogen bonding and hydrophobic interfaces and high overall shape complementary to the ligand, and use it to design protein binding sites for the steroid digoxigenin (DIG). Of 17 designs that were experimentally characterized, two bind DIG; the highest affinity design has the lowest predicted interaction energy and the most pre-organized binding site in the set. A comprehensive binding-fitness landscape of this design generated by library selection and deep sequencing was used to guide optimization of binding affinity to a picomolar level, and two X-ray co-crystal structures of optimized complexes show atomic level agreement with the design models. The designed binder has a high selectivity for DIG over the related steroids digitoxigenin, progesterone, and β-estradiol, which can be reprogrammed through the designed hydrogen-bonding interactions. Taken together, the binding fitness landscape, co-crystal structures, and thermodynamic binding parameters illustrate how increases in binding affinity can result from distal sequence changes that limit the protein ensemble to conformers making the most energetically favorable interactions with the ligand. The computational design method presented here should enable the development of a new generation of biosensors, therapeutics, and diagnostics. PMID:24005320

Study of the growth and pyroelectric properties of TGS crystals doped with aniline-family dipolar molecules

NASA Astrophysics Data System (ADS)

Zhang, Kecong; Song, Jiancheng; Wang, Min; Fang, Changshui; Lu, Mengkai

1987-04-01

TGS crystals doped with aniline-family dipolar molecules (aniline, 2-aminobenzoic acid, 3-aminobenzoic acid, 3-aminobenzene-sulphonic acid, 4-aminobenzenesulphonic acid and 4-nitroraniline) have been grown by the slow-cooling solution method. The influence of these dopants on the growth habits, crystal morphology pyroelectric properties, and structure parameters of TGS crystals has been systematically investigated. The effects of the domain structure of the seed crystal on the pyroelectric properties of the doped crystals have been studied. It is found that the spontaneous polarization (P), pyroelectric coefficient (lambda), and internal bias field of the doped crystals are slightly higher than those of the pure TGS, and the larger the dipole moment of the dopant molecule, the higher the P and lambda of the doped TGS crystal.

Positioning and joining of organic single-crystalline wires

PubMed Central

Wu, Yuchen; Feng, Jiangang; Jiang, Xiangyu; Zhang, Zhen; Wang, Xuedong; Su, Bin; Jiang, Lei

2015-01-01

Organic single-crystal, one-dimensional materials can effectively carry charges and/or excitons due to their highly ordered molecule packing, minimized defects and eliminated grain boundaries. Controlling the alignment/position of organic single-crystal one-dimensional architectures would allow on-demand photon/electron transport, which is a prerequisite in waveguides and other optoelectronic applications. Here we report a guided physical vapour transport technique to control the growth, alignment and positioning of organic single-crystal wires with the guidance of pillar-structured substrates. Submicrometre-wide, hundreds of micrometres long, highly aligned, organic single-crystal wire arrays are generated. Furthermore, these organic single-crystal wires can be joined within controlled angles by varying the pillar geometries. Owing to the controllable growth of organic single-crystal one-dimensional architectures, we can present proof-of-principle demonstrations utilizing joined wires to allow optical waveguide through small radii of curvature (internal angles of ~90–120°). Our methodology may open a route to control the growth of organic single-crystal one-dimensional materials with potential applications in optoelectronics. PMID:25814032

Crystals in light.

PubMed

Kahr, Bart; Freudenthal, John; Gunn, Erica

2010-05-18

We have made images of crystals illuminated with polarized light for almost two decades. Early on, we abandoned photosensitive chemicals in favor of digital electrophotometry with all of the attendant advantages of quantitative intensity data. Accurate intensities are a boon because they can be used to analytically discriminate small effects in the presence of larger ones. The change in the form of our data followed camera technology that transformed picture taking the world over. Ironically, exposures in early photographs were presumed to correlate simply with light intensity, raising the hope that photography would replace sensorial interpretation with mechanical objectivity and supplant the art of visual photometry. This was only true in part. Quantitative imaging accurate enough to render the separation of crystalloptical quantities had to await the invention of the solid-state camera. Many pioneers in crystal optics were also major figures in the early history of photography. We draw out the union of optical crystallography and photography because the tree that connects the inventors of photography is a structure unmatched for organizing our work during the past 20 years, not to mention that silver halide crystallites used in chemical photography are among the most consequential "crystals in light", underscoring our title. We emphasize crystals that have acquired optical properties such as linear birefringence, linear dichroism, circular birefringence, and circular dichroism, during growth from solution. Other crystalloptical effects were discovered that are unique to curiously dissymmetric crystals containing embedded oscillators. In the aggregate, dyed crystals constitute a generalization of single crystal matrix isolation. Simple crystals provided kinetic stability to include guests such as proteins or molecules in excited states. Molecular lifetimes were extended for the preparation of laser gain media and for the study of the photodynamics of single molecules. Luminophores were used as guests in crystals to reveal aspects of growth mechanisms by labeling surface structures such as steps and kinks. New methods were adopted for measuring and imaging the optical rotatory power of crystals. Chiroptical anisotropies can now be compared with the results of quantum chemical calculations that have emerged in the past 10 years. The rapid determination of the optical rotation and circular dichroism tensors of molecules in crystals, and the interpretation of these anisotropies, remains a subject of future research. Polycrystalline patterns that form far from equilibrium challenged the quantitative interpretation of micrographs when heterogeneities along the optical path and obliquely angled interfaces played large roles. Resulting "artifacts" were nevertheless incisive probes of polycrystalline texture and mesoscale chemistry in simple substances grown far from equilibrium or in biopathological crystals such as Alzheimer's amyloid plaques.

SAXS-WAXS studies of the low-resolution structure in solution of xylose/glucose isomerase from Streptomyces rubiginosus

NASA Astrophysics Data System (ADS)

Kozak, Maciej; Taube, Michał

2009-10-01

The structure and conformation of molecule of xylose/glucose isomerase from Streptomyces rubiginosus in solution (at pH 6 and 7.6; with and without the substrate) has been studied by small- and wide-angle scattering of synchrotron radiation (SAXS-WAXS). On the basis of the SAXS-WAXS data, the low-resolution structure in solution has been reconstructed using ab inito methods. A comparison of the models of glucose isomerase shows only small differences between the model in solution and the crystal structure.

Correlation of Intermolecular Acyl Transfer Reactivity with Noncovalent Lattice Interactions in Molecular Crystals: Toward Prediction of Reactivity of Organic Molecules in the Solid State.

PubMed

Krishnaswamy, Shobhana; Shashidhar, Mysore S

2018-04-06

Intermolecular acyl transfer reactivity in several molecular crystals was studied, and the outcome of the reactivity was analyzed in the light of structural information obtained from the crystals of the reactants. Minor changes in the molecular structure resulted in significant variations in the noncovalent interactions and packing of molecules in the crystal lattice, which drastically affected the facility of the intermolecular acyl transfer reactivity in these crystals. Analysis of the reactivity vs crystal structure data revealed dependence of the reactivity on electrophile···nucleophile interactions and C-H···π interactions between the reacting molecules. The presence of these noncovalent interactions augmented the acyl transfer reactivity, while their absence hindered the reactivity of the molecules in the crystal. The validity of these correlations allows the prediction of intermolecular acyl transfer reactivity in crystals and co-crystals of unknown reactivity. This crystal structure-reactivity correlation parallels the molecular structure-reactivity correlation in solution-state reactions, widely accepted as organic functional group transformations, and sets the stage for the development of a similar approach for reactions in the solid state.

Annular tautomerism: experimental observations and quantum mechanics calculations.

PubMed

Cruz-Cabeza, Aurora J; Schreyer, Adrian; Pitt, William R

2010-06-01

The use of MP2 level quantum mechanical (QM) calculations on isolated heteroaromatic ring systems for the prediction of the tautomeric propensities of whole molecules in a crystalline environment was examined. A Polarisable Continuum Model was used in the calculations to account for environment effects on the tautomeric relative stabilities. The calculated relative energies of tautomers were compared to relative abundances within the Cambridge Structural Database (CSD) and the Protein Data Bank (PDB). The work was focussed on 84 annular tautomeric forms of 34 common ring systems. Good agreement was found between the calculations and the experimental data even if the quantity of these data was limited in many cases. The QM results were compared to those produced by much faster semiempirical calculations. In a search for other sources of the useful experimental data, the relative numbers of known compounds in which prototropic positions were often substituted by heavy atoms were also analysed. A scheme which groups all annular tautomeric transformations into 10 classes was developed. The scheme was designed to encompass a comprehensive set of known and theoretically possible tautomeric ring systems generated as part of a previous study. General trends across analogous ring systems were detected as a result. The calculations and statistics collected on crystallographic data as well as the general trends observed should be useful for the better modelling of annular tautomerism in the applications such as computer-aided drug design, small molecule crystal structure prediction, the naming of compounds and the interpretation of protein-small molecule crystal structures.

Annular tautomerism: experimental observations and quantum mechanics calculations

NASA Astrophysics Data System (ADS)

Cruz-Cabeza, Aurora J.; Schreyer, Adrian; Pitt, William R.

2010-06-01

The use of MP2 level quantum mechanical (QM) calculations on isolated heteroaromatic ring systems for the prediction of the tautomeric propensities of whole molecules in a crystalline environment was examined. A Polarisable Continuum Model was used in the calculations to account for environment effects on the tautomeric relative stabilities. The calculated relative energies of tautomers were compared to relative abundances within the Cambridge Structural Database (CSD) and the Protein Data Bank (PDB). The work was focussed on 84 annular tautomeric forms of 34 common ring systems. Good agreement was found between the calculations and the experimental data even if the quantity of these data was limited in many cases. The QM results were compared to those produced by much faster semiempirical calculations. In a search for other sources of the useful experimental data, the relative numbers of known compounds in which prototropic positions were often substituted by heavy atoms were also analysed. A scheme which groups all annular tautomeric transformations into 10 classes was developed. The scheme was designed to encompass a comprehensive set of known and theoretically possible tautomeric ring systems generated as part of a previous study. General trends across analogous ring systems were detected as a result. The calculations and statistics collected on crystallographic data as well as the general trends observed should be useful for the better modelling of annular tautomerism in the applications such as computer-aided drug design, small molecule crystal structure prediction, the naming of compounds and the interpretation of protein—small molecule crystal structures.

The Cambridge Structural Database: a quarter of a million crystal structures and rising.

PubMed

Allen, Frank H

2002-06-01

The Cambridge Structural Database (CSD) now contains data for more than a quarter of a million small-molecule crystal structures. The information content of the CSD, together with methods for data acquisition, processing and validation, are summarized, with particular emphasis on the chemical information added by CSD editors. Nearly 80% of new structural data arrives electronically, mostly in CIF format, and the CCDC acts as the official crystal structure data depository for 51 major journals. The CCDC now maintains both a CIF archive (more than 73,000 CIFs dating from 1996), as well as the distributed binary CSD archive; the availability of data in both archives is discussed. A statistical survey of the CSD is also presented and projections concerning future accession rates indicate that the CSD will contain at least 500,000 crystal structures by the year 2010.

Structural studies of bean pod mottle virus, capsid, and RNA in crystal and solution states by laser Raman spectroscopy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Tiansheng; Thomas, G.J. Jr.; Chen, Zhongguo

Structures of protein and RNA components of bean pod mottle virus (BPMV) have been investigated by use of laser Raman spectroscopy. Raman spectra were collected from both aqueous solutions and single crystals of BPMV capsids (top component) and virions (middle and bottom components, which package, respectively, small and large RNA molecules). Analysis of the data permits the assignment of conformation-sensitive Raman bands to viral protein and RNA constituents and observation of structural similarities and differences between solution and crystalline states of BPMV components. The Raman results show that the protein subunits of the empty capsid contain between 45% and 55%more » {beta}-strand and {beta}-turn secondary structure, in agreement with the recently determined X-ray crystal structure, and that this total {beta}-strand content undergoes a small increase with packaging of RNA. A comparison of Raman spectra of crystal and solution states of the BPMV middle component reveals only minor structural differences between the two, and these are restricted almost exclusively to Raman bands of RNA in the region of assigned phosphodiester conformation markers. Although in both the crystal and solution only C3{prime} endo/anti nucleosides are detected, the crystal exhibits a weaker 813-cm{sup {minus}1} band and strong 870-cm{sup {minus}1} band, which suggests that {approximately}8% of the nucleotides have O-P-O torsions configured differently in the crystal from that in the solution.« less

Optimization of crystals from nanodrops: crystallization and preliminary crystallographic study of a pheromone-binding protein from the honeybee Apis mellifera L.

PubMed

Lartigue, Audrey; Gruez, Arnaud; Briand, Loïc; Pernollet, Jean-Claude; Spinelli, Silvia; Tegoni, Mariella; Cambillau, Christian

2003-05-01

Pheromone-binding proteins (PBPs) are small helical proteins ( approximately 13-17 kDa) present in various sensory organs from moths and other insect species. They are involved in the transport of pheromones from the sensillar lymph to the olfactory receptors. Here, crystals of a PBP (Amel-ASP1) originating from honeybee (Apis mellifera L.) antennae and expressed as recombinant protein using the yeast Pichia pastoris are reported. Crystals of Amel-ASP1 have been obtained by the sitting-drop vapour-diffusion method using a nanodrop-dispensing robot under the following conditions: 200 nl of 40 mg ml(-1) protein solution in 10 mM Tris, 25 mM NaCl pH 8.0 was mixed with 100 nl of well solution containing 0.15 M sodium citrate, 1.5 M ammonium sulfate pH 5.5. The protein crystallizes in space group C222(1), with unit-cell parameters a = 74.8, b = 85.8, c = 50.2 A. With one molecule in the asymmetric unit, V(M) is 3.05 A(3) Da(-1) and the solvent content is 60%. A complete data set has been collected at 1.6 A resolution on beamline ID14-2 (ESRF, Grenoble). The nanodrop crystallization technique used with a novel optimization procedure made it possible to consume small amounts of protein and to obtain a unique crystal per nanodrop, suitable directly for data collection in-house or at a synchrotron-radiation source.

Monte Carlo study of disorder in HMTA

NASA Astrophysics Data System (ADS)

Goossens, D. J.; Welberry, T. R.

2001-12-01

We investigate disordered solids by automated fitting of a Monte Carlo simulation of a crystal to observed single-crystal diffuse X-ray scattering. This method has been extended to the study of crystals of relatively large organic molecules by using a z-matrix to describe the molecules. This allows exploration of motions within molecules. We refer to the correlated thermal motion observed in benzil, and to the occupational and thermal disorder in the 1:1 adduct of hexamethylenetetramine and azelaic acid, HMTA. The technique is capable of giving insight into modes of vibration within molecules and correlated motions between molecules.

Structural Studies on Intact Clostridium botulinum Neurotoxins Complexed with Inhibitors Leading to Drug Design

DTIC Science & Technology

2008-02-01

via virtual screening. These compounds include small molecules – transition state analogues and benzimidazoles . We have determined the crystal...project period. It has been established that benzimidazole compounds are good zinc chealators and since botulinum neurotoxin catalytic domains are zinc...endopeptidases we first selected a subset of compounds containing benzimidazole moieties. We pulled out nearly 9000 compound containing both

Fragment-based screening of the bromodomain of ATAD2

DOE PAGES

Harner, Mary J.; Chauder, Brian A.; Phan, Jason; ...

2014-10-14

Cellular and genetic evidence suggest that inhibition of ATAD2 could be a useful strategy to treat several types of cancer. To discover small-molecule inhibitors of the bromodomain of ATAD2, we used a fragment-based approach. As a result, fragment hits were identified using NMR spectroscopy, and ATAD2 was crystallized with three of the hits identified in the fragment screen.

Pure white OLED based on an organic small molecule: 2,6-Di(1H-benzo[d]imidazol-2-yl)pyridine

NASA Astrophysics Data System (ADS)

Liu, Jian

2015-10-01

2,6-Di(1H-benzo[d]imidazol-2-yl)pyridine (DBIP) was synthesized. The single-crystal structure of DBIP was resolved. DBIP-based OLED was fabricated. The electroluminescence for the device corresponds to a pure white emission. In addition, thermal stability, UV-vis, photoluminescence and electrochemical behaviors of DBIP were investigated as well.

The 2D Selfassembly of Benzimidazole and its Co-crystallization

NASA Astrophysics Data System (ADS)

Costa, Paulo; Teeter, Jacob; Kunkel, Donna; Sinitskii, Alexander; Enders, Axel

Benzimidazoles (BI) are organic molecules that form ferroelectric crystals. Key to their ferroelectric behavior are the switchable N . . . HN type bonds and how they couple to the electron system of the molecules. We attempted to crystallize BI on various metal surfaces and studied them using STM. We observed that on Au and Ag, BI joins into zipper chains characteristic of its bulk structure that can pack into a continuous 2D layer. Because the dipole of BI lies in the direction of its switchable hydrogen bond, these zippers should in principle have reversible polarizations that point along the direction they run. BI's crystallization is reminiscent to how croconic acid (CA) crystallizes in 2D using O . . . HO bonding, suggesting that these molecules may be able to co-crystallize through OH . . . N bonds. This would present the opportunity to modify BI's properties, such as the energy needed to switch a hydrogen from a donor to acceptor site. When co-deposited, CA and BI successfully combine into a co-crystal formed by building blocks consisting of 2 CA and 2 BI molecules. These findings demonstrate the usefulness of using STM as a preliminary check to verify if two molecules are compatible with each other without having to attempt crystallization with multiple solvents and mixing methods.

Use of Crystal Structure Informatics for Defining the Conformational Space Needed for Predicting Crystal Structures of Pharmaceutical Molecules.

PubMed

Iuzzolino, Luca; Reilly, Anthony M; McCabe, Patrick; Price, Sarah L

2017-10-10

Determining the range of conformations that a flexible pharmaceutical-like molecule could plausibly adopt in a crystal structure is a key to successful crystal structure prediction (CSP) studies. We aim to use conformational information from the crystal structures in the Cambridge Structural Database (CSD) to facilitate this task. The conformations produced by the CSD Conformer Generator are reduced in number by considering the underlying rotamer distributions, an analysis of changes in molecular shape, and a minimal number of molecular ab initio calculations. This method is tested for five pharmaceutical-like molecules where an extensive CSP study has already been performed. The CSD informatics-derived set of crystal structure searches generates almost all the low-energy crystal structures previously found, including all experimental structures. The workflow effectively combines information on individual torsion angles and then eliminates the combinations that are too high in energy to be found in the solid state, reducing the resources needed to cover the solid-state conformational space of a molecule. This provides insights into how the low-energy solid-state and isolated-molecule conformations are related to the properties of the individual flexible torsion angles.

Plastically bendable crystals of probenecid and its cocrystal with 4,4‧-Bipyridine

NASA Astrophysics Data System (ADS)

Nath, Naba K.; Hazarika, Mousumi; Gupta, Poonam; Ray, Nisha R.; Paul, Amit K.; Nauha, Elisa

2018-05-01

Recent findings of plastically bendable molecular crystals led to the realization that design based strategies are required for these materials to be useful in real life application. We have coincidentally discovered plastically bendable crystals of a drug molecule probenecid. Based on the structural features of its crystals at room temperature, we hypothesized that introduction of a molecular spacer between two hydrogen bonded molecules of probenecid, by replacing the carboxylic acid homodimer with similar dimeric hydrogen bonding synthon, would not disturb the layered molecular packing of probenecid. As a consequence, the new multi-component crystal would retain flexibility similar to the original probenecid crystals. Herein we have attempted to prove this hypothesis and we were successful in the case of probenecid: 4,4‧-bipyridine cocrystal. As designed, in the crystal structure 4,4‧-bypyridine molecule acted as spacer and connected two probenecid molecules resulting in the retention of the slip planes which are necessary for a molecular crystal to be plastically bendable. DFT computational calculations were carried out to account for the hydrogen bonding synthons between probenecid and the coformers under study.

Crystal engineering of ibuprofen compounds: From molecule to crystal structure to morphology prediction by computational simulation and experimental study

NASA Astrophysics Data System (ADS)

Zhang, Min; Liang, Zuozhong; Wu, Fei; Chen, Jian-Feng; Xue, Chunyu; Zhao, Hong

2017-06-01

We selected the crystal structures of ibuprofen with seven common space groups (Cc, P21/c, P212121, P21, Pbca, Pna21, and Pbcn), which was generated from ibuprofen molecule by molecular simulation. The predicted crystal structures of ibuprofen with space group P21/c has the lowest total energy and the largest density, which is nearly indistinguishable with experimental result. In addition, the XRD patterns for predicted crystal structure are highly consistent with recrystallization from solvent of ibuprofen. That indicates that the simulation can accurately predict the crystal structure of ibuprofen from the molecule. Furthermore, based on this crystal structure, we predicted the crystal habit in vacuum using the attachment energy (AE) method and considered solvent effects in a systematic way using the modified attachment energy (MAE) model. The simulation can accurately construct a complete process from molecule to crystal structure to morphology prediction. Experimentally, we observed crystal morphologies in four different polarity solvents compounds (ethanol, acetonitrile, ethyl acetate, and toluene). We found that the aspect ratio decreases of crystal habits in this ibuprofen system were found to vary with increasing solvent relative polarity. Besides, the modified crystal morphologies are in good agreement with the observed experimental morphologies. Finally, this work may guide computer-aided design of the desirable crystal morphology.

Atomic force microscopy study on crystal growth of Cu 2+-doped L-arginine phosphate monohydrate crystals

NASA Astrophysics Data System (ADS)

Geng, Y. L.; Xu, D.; Wang, Y. L.; Du, W.; Liu, H. Y.; Zhang, G. H.; Wang, X. Q.; Sun, D. L.

2005-01-01

Sub-steps and defects of the {1 0 0} planes of Cu 2+-doped L-arginine phosphate monohydrate (LAP) crystals are observed by atomic force microscopy. Formation of sub-steps is not due to the stacking faults but a result of single LAP: Cu 2+ molecule acting as growth unit. Two-dimensional (2D) nuclei with the same height as sub-steps occur on the step-edges. Impurities of Cu 2+ ions cause steps bunch and macrosteps formation. Liquid inclusions in the form of long channels form when the macrosteps lose their stability. Numerous small 3D growth hillocks are found in the channels. The extra stress induced by the 3D islands can result in dislocations and steps mismatches.

Neutron scattering studies of molecular conformations in liquid crystal polymers

NASA Astrophysics Data System (ADS)

Noirez, L.; Moussa, F.; Cotton, J. P.; Keller, P.; Pépy, G.

1991-03-01

A comblike liquid crystal polymer (LPC) is a polymer on which mesogenic molecules have been grafted. It exhibits a succession of liquid crystal phases. Usually the equilibrium conformation of an ordinary polymeric chain corresponds to a maximum entropy, i.e., to an isotropic spherical coil. How does the backbone of a LCP behave in the nematic and smectic field? Small-angle neutron scattering may answer this question. Such measurements are presented here on four different polymers as a function of temperature. An anisotropy of the backbone conformation is found in all these studied compounds, much more pronounced in the smectic phase than in the nematic phase: the backbone spreads more or less perpendicularly to its hanging cores. A comparison with existing theories and a discussion of these results is outlined.

Metal-assisted and microwave accelerated-evaporative crystallization: Application to lysozyme protein

NASA Astrophysics Data System (ADS)

Mauge-Lewis, Kevin

In response to the growing need for new crystallization techniques that afford for rapid processing times along with control over crystal size and distribution, the Aslan Research Group has recently demonstrated the use of Metal-Assisted and Microwave-Accelerated Evaporative Crystallization MA-MAEC technique in conjunction with metal nanoparticles and nanostructures for the crystallization of amino acids and organic small molecules. In this study, we have employed the newly developed MA-MAEC technique to the accelerated crystallization of chicken egg-white lysozyme on circular crystallization platforms in order to demonstrate the proof-of-principle application of the method for protein crystallization. The circular crystallization platforms are constructed in-house from poly (methyl methacrylate) (PMMA) and silver nanoparticle films (SNFs), indium tin oxide (ITO) and iron nano-columns. In this study, we prove the MA-MAEC method to be a more effective technique in the rapid crystallization of macromolecules in comparison to other conventional methods. Furthermore, we demonstrate the use of the novel iCrystal system, which incorporates the use of continuous, low wattage heating to facilitate the rapid crystallization of the lysozyme while still retaining excellent crystal quality. With the incorporation of the iCrystal system, we observe crystallization times that are even shorter than those produced by the MA-MAEC technique using a conventional microwave oven in addition to significantly improved crystal quality.

Observation of Spectral Diffusion in Crystals Using Single Impurity Molecules

DTIC Science & Technology

1990-10-31

from 12pentacene photophysical parameters including intersystem crossing . Apparently (and not surprisingly), the local pentacene environment this... pentacene molecules inp-terphenyl, both stable as well as spectrally diffusing single molecules can be observed. 20 DISTRIBUTION/AVAILABILITY OF ABSTRACT 121...with ultrathin sublimed crystals have removed this obstacle. For the case of pentacene impurities in crystals of p-terphenyl, we observe two radically

3-Dimensional Protein Structure of Influenza

NASA Technical Reports Server (NTRS)

2004-01-01

The loss of productivity due to flu is staggering. Costs range as much as $20 billio a year. High mutation rates of the flu virus have hindered development of new drugs or vaccines. The secret lies in a small molecule which is attached to the host cell's surface. Each flu virus, no matter what strain, must remove this small molecule to escape the host cell to spread infection. Using data from space and earth grown crystals, researchers from the Center of Macromolecular Crystallography (CMC) are desining drugs to bind with this protein's active site. This lock and key fit reduces the spread of flu in the body by blocking its escape route. In collaboration with its corporate partner, the CMC has refined drug structure in preparation for clinical trials. Tested and approved relief is expected to reach drugstores by year 2004.

Charge Transport Properties of Durene Crystals from First-Principles.

PubMed

Motta, Carlo; Sanvito, Stefano

2014-10-14

We establish a rigorous computational scheme for constructing an effective Hamiltonian to be used for the determination of the charge carrier mobility of pure organic crystals at finite temperature, which accounts for van der Waals interactions, and it includes vibrational contributions from the entire phonon spectrum of the crystal. Such an approach is based on the ab initio framework provided by density functional theory and the construction of a tight-binding effective model via Wannier transformation. The final Hamiltonian includes coupling of the electrons to the crystals phonons, which are also calculated from density functional theory. We apply this methodology to the case of durene, a small π-conjugated molecule, which forms a high-mobility herringbone-stacked crystal. We show that accounting correctly for dispersive forces is fundamental for obtaining a high-quality phonon spectrum, in agreement with experiments. Then, the mobility as a function of temperature is calculated along different crystallographic directions and the phonons most responsible for the scattering are identified.

Efficient one-cycle affinity selection of binding proteins or peptides specific for a small-molecule using a T7 phage display pool.

PubMed

Takakusagi, Yoichi; Kuramochi, Kouji; Takagi, Manami; Kusayanagi, Tomoe; Manita, Daisuke; Ozawa, Hiroko; Iwakiri, Kanako; Takakusagi, Kaori; Miyano, Yuka; Nakazaki, Atsuo; Kobayashi, Susumu; Sugawara, Fumio; Sakaguchi, Kengo

2008-11-15

Here, we report an efficient one-cycle affinity selection using a natural-protein or random-peptide T7 phage pool for identification of binding proteins or peptides specific for small-molecules. The screening procedure involved a cuvette type 27-MHz quartz-crystal microbalance (QCM) apparatus with introduction of self-assembled monolayer (SAM) for a specific small-molecule immobilization on the gold electrode surface of a sensor chip. Using this apparatus, we attempted an affinity selection of proteins or peptides against synthetic ligand for FK506-binding protein (SLF) or irinotecan (Iri, CPT-11). An affinity selection using SLF-SAM and a natural-protein T7 phage pool successfully detected FK506-binding protein 12 (FKBP12)-displaying T7 phage after an interaction time of only 10 min. Extensive exploration of time-consuming wash and/or elution conditions together with several rounds of selection was not required. Furthermore, in the selection using a 15-mer random-peptide T7 phage pool and subsequent analysis utilizing receptor ligand contact (RELIC) software, a subset of SLF-selected peptides clearly pinpointed several amino-acid residues within the binding site of FKBP12. Likewise, a subset of Iri-selected peptides pinpointed part of the positive amino-acid region of residues from the Iri-binding site of the well-known direct targets, acetylcholinesterase (AChE) and carboxylesterase (CE). Our findings demonstrate the effectiveness of this method and general applicability for a wide range of small-molecules.

Tailor-made force fields for crystal-structure prediction.

PubMed

Neumann, Marcus A

2008-08-14

A general procedure is presented to derive a complete set of force-field parameters for flexible molecules in the crystalline state on a case-by-case basis. The force-field parameters are fitted to the electrostatic potential as well as to accurate energies and forces generated by means of a hybrid method that combines solid-state density functional theory (DFT) calculations with an empirical van der Waals correction. All DFT calculations are carried out with the VASP program. The mathematical structure of the force field, the generation of reference data, the choice of the figure of merit, the optimization algorithm, and the parameter-refinement strategy are discussed in detail. The approach is applied to cyclohexane-1,4-dione, a small flexible ring. The tailor-made force field obtained for cyclohexane-1,4-dione is used to search for low-energy crystal packings in all 230 space groups with one molecule per asymmetric unit, and the most stable crystal structures are reoptimized in a second step with the hybrid method. The experimental crystal structure is found as the most stable predicted crystal structure both with the tailor-made force field and the hybrid method. The same methodology has also been applied successfully to the four compounds of the fourth CCDC blind test on crystal-structure prediction. For the five aforementioned compounds, the root-mean-square deviations between lattice energies calculated with the tailor-made force fields and the hybrid method range from 0.024 to 0.053 kcal/mol per atom around an average value of 0.034 kcal/mol per atom.

EPR Studies of Magnetically Dilute Ga-Doped Single Crystals of Fe18 Antiferromagnetic Molecular Wheels

NASA Astrophysics Data System (ADS)

Henderson, John; Ramsey, Christopher; Del Barco, Enrique; Stamatatos, Theocharis; Christou, George

2008-03-01

Studies of the quantum dynamics of the electron spins in solid state systems has gained considerable interest recently due to their potential for use as quantum computing substrates. One class of materials, molecular magnets, are of particular importance, owing to the seemingly limitless array of spin configurations due to synthetic chemical flexibility. Efforts are currently devoted to minimizing decoherence times by diminishing dipolar effects. In this regard, we have carried out EPR measurements on small single crystals of 0.5% Ga doped Fe18 molecular antiferromagnetic wheels at temperatures down to 300 mK using planar resonators patterned on GaAs wafers. This system constitutes a dilute sample of S = 5/2 molecules dispersed within a sea of S = 0 (at low temperature) molecules, which significantly reduces dipolar interactions and might provide a means of observing Rabi oscillations in crystals of molecular magnets. Detailed angular dependence studies reveal significant anisotropy with D = 500 mK and E = 20 mK. The presence of second order anisotropy (E) is very unusual for such a high symmetry system and its interpretation will be discussed. Pulsed-EPR measurements and doping concentration dependence will also be discussed.

Anomalous doping of a molecular crystal monitored with confocal fluorescence microscopy: Terrylene in a p-terphenyl crystal

NASA Astrophysics Data System (ADS)

Białkowska, Magda; Deperasińska, Irena; Makarewicz, Artur; Kozankiewicz, Bolesław

2017-09-01

Highly terrylene doped single crystals of p-terphenyl, obtained by co-sublimation of both components, showed bright spots in the confocal fluorescence images. Polarization of the fluorescence excitation spectra, blinking and bleaching, and saturation behavior allowed us to attribute them to single molecules of terrylene anomalously embedded between two neighbor layers of the host crystal, in the (a,b) plane. Such an orientation of terrylene molecules results in much more efficient absorption and collection of the fluorescence photons than in the case of previously investigated molecules embedded in the substitution sites. The above conclusion was supported by quantum chemistry calculations. We postulate that the kind of doping considered in this work should be possible in other molecular crystals where the host molecules are organized in a herringbone pattern.

Crystal Nucleation Using Surface-Energy-Modified Glass Substrates.

PubMed

Nordquist, Kyle A; Schaab, Kevin M; Sha, Jierui; Bond, Andrew H

2017-08-02

Systematic surface energy modifications to glass substrates can induce nucleation and improve crystallization outcomes for small molecule active pharmaceutical ingredients (APIs) and proteins. A comparatively broad probe for function is presented in which various APIs, proteins, organic solvents, aqueous media, surface energy motifs, crystallization methods, form factors, and flat and convex surface energy modifications were examined. Replicate studies ( n ≥ 6) have demonstrated an average reduction in crystallization onset times of 52(4)% (alternatively 52 ± 4%) for acetylsalicylic acid from 91% isopropyl alcohol using two very different techniques: bulk cooling to 0 °C using flat surface energy modifications or microdomain cooling to 4 °C from the interior of a glass capillary having convex surface energy modifications that were immersed in the solution. For thaumatin and bovine pancreatic trypsin, a 32(2)% reduction in crystallization onset times was demonstrated in vapor diffusion experiments ( n ≥ 15). Nucleation site arrays have been engineered onto form factors frequently used in crystallization screening, including microscope slides, vials, and 96- and 384-well high-throughput screening plates. Nucleation using surface energy modifications on the vessels that contain the solutes to be crystallized adds a layer of useful variables to crystallization studies without requiring significant changes to workflows or instrumentation.

Unique Crystallization of Fullerenes: Fullerene Flowers

PubMed Central

Kim, Jungah; Park, Chibeom; Song, Intek; Lee, Minkyung; Kim, Hyungki; Choi, Hee Cheul

2016-01-01

Solution-phase crystallization of fullerene molecules strongly depends on the types of solvent and their ratios because solvent molecules are easily included in the crystal lattice and distort its structure. The C70 (solute)–mesitylene (solvent) system yields crystals with various morphologies and structures, such as cubes, tubes, and imperfect rods. Herein, using C60 and C70 dissolved in mesitylene, we present a novel way to grow unique flower-shaped crystals with six symmetric petals. The different solubility of C60 and C70 in mesitylene promotes nucleation of C70 with sixfold symmetry in the early stage, which is followed by co-crystallization of both C60 and C70 molecules, leading to lateral petal growth. Based on the growth mechanism, we obtained more complex fullerene crystals, such as multi-deck flowers and tube-flower complexes, by changing the sequence and parameters of crystallization. PMID:27561446

Cooperative enhancement of the nonlinear optical response in conjugated energetic materials: A TD-DFT study

DOE PAGES

Sifain, Andrew E.; Tadesse, Loza F.; Bjorgaard, Josiah August; ...

2017-03-21

Conjugated energetic molecules (CEMs) are a class of explosives with high nitrogen content that posses both enhanced safety and energetic performance properties and are ideal for direct optical initiation. As isolated molecules, they absorb within the range of conventional lasers. Crystalline CEMs are used in practice, however, and their properties can differ due to intermolecular interaction. Herein, time-dependent density functional theory was used to investigate one-photon absorption (OPA) and two-photon absorption (TPA) of monomers and dimers obtained from experimentally determined crystal structures of CEMs. OPA scales linearly with the number of chromophore units, while TPA scales nonlinearly, where a moremore » than 3-fold enhancement in peak intensity, per chromophore unit, is calculated. Cooperative enhancement depends on electronic delocalization spanning both chromophore units. An increase in sensitivity to nonlinear laser initiation makes these materials suitable for practical use. This is the first study predicting a cooperative enhancement of the nonlinear optical response in energetic materials composed of relatively small molecules. Finally, the proposed model quantum chemistry is validated by comparison to crystal structure geometries and the optical absorption of these materials dissolved in solution.« less

DNA sequence analysis with droplet-based microfluidics

PubMed Central

Abate, Adam R.; Hung, Tony; Sperling, Ralph A.; Mary, Pascaline; Rotem, Assaf; Agresti, Jeremy J.; Weiner, Michael A.; Weitz, David A.

2014-01-01

Droplet-based microfluidic techniques can form and process micrometer scale droplets at thousands per second. Each droplet can house an individual biochemical reaction, allowing millions of reactions to be performed in minutes with small amounts of total reagent. This versatile approach has been used for engineering enzymes, quantifying concentrations of DNA in solution, and screening protein crystallization conditions. Here, we use it to read the sequences of DNA molecules with a FRET-based assay. Using probes of different sequences, we interrogate a target DNA molecule for polymorphisms. With a larger probe set, additional polymorphisms can be interrogated as well as targets of arbitrary sequence. PMID:24185402

Protein Crystallization.

PubMed

McPherson, Alexander

2017-01-01

Protein crystallization was discovered by chance nearly 200 years ago and was developed in the late nineteenth century as a powerful purification tool, and a demonstration of chemical purity. The crystallization of proteins, nucleic acids, and large biological complexes, such as viruses, depends on the creation of a solution that is supersaturated in the macromolecule, but exhibits conditions that do not significantly perturb its natural state. Supersaturation is produced through the addition of mild precipitating agents such as neutral salts or polymers, and by manipulation of various parameters that include temperature, ionic strength, and pH. Also important in the crystallization process are factors that can affect the structural state of the macromolecule, such as metal ions, inhibitors, cofactors, or other conventional small molecules. A variety of approaches have been developed that combine the spectrum of factors that effect and promote crystallization, and among the most widely used are vapor diffusion, dialysis, batch, and liquid-liquid diffusion. Successes in macromolecular crystallization have multiplied rapidly in recent years due to the advent of practical, easy-to-use screening kits, and the application of laboratory robotics.

Surface reengineering of RPA70N enables cocrystallization with an inhibitor of the replication protein A interaction motif of ATR interacting protein.

PubMed

Feldkamp, Michael D; Frank, Andreas O; Kennedy, J Phillip; Patrone, James D; Vangamudi, Bhavatarini; Waterson, Alex G; Fesik, Stephen W; Chazin, Walter J

2013-09-17

Replication protein A (RPA) is the primary single-stranded DNA (ssDNA) binding protein in eukaryotes. The N-terminal domain of the RPA70 subunit (RPA70N) interacts via a basic cleft with a wide range of DNA processing proteins, including several that regulate DNA damage response and repair. Small molecule inhibitors that disrupt these protein-protein interactions are therefore of interest as chemical probes of these critical DNA processing pathways and as inhibitors to counter the upregulation of DNA damage response and repair associated with treatment of cancer patients with radiation or DNA-damaging agents. Determination of three-dimensional structures of protein-ligand complexes is an important step for elaboration of small molecule inhibitors. However, although crystal structures of free RPA70N and an RPA70N-peptide fusion construct have been reported, RPA70N-inhibitor complexes have been recalcitrant to crystallization. Analysis of the P61 lattice of RPA70N crystals led us to hypothesize that the ligand-binding surface was occluded. Surface reengineering to alter key crystal lattice contacts led to the design of RPA70N E7R, E100R, and E7R/E100R mutants. These mutants crystallized in a P212121 lattice that clearly had significant solvent channels open to the critical basic cleft. Analysis of X-ray crystal structures, target peptide binding affinities, and (15)N-(1)H heteronuclear single-quantum coherence nuclear magnetic resonance spectra showed that the mutations do not result in perturbations of the RPA70N ligand-binding surface. The success of the design was demonstrated by determining the structure of RPA70N E7R soaked with a ligand discovered in a previously reported molecular fragment screen. A fluorescence anisotropy competition binding assay revealed this compound can inhibit the interaction of RPA70N with the peptide binding motif from the DNA damage response protein ATRIP. The implications of the results are discussed in the context of ongoing efforts to design RPA70N inhibitors.

Nucleation and Crystallization of Globular Proteins: What we Know and What is Missing

NASA Technical Reports Server (NTRS)

Rosenberger, F.; Vekilov, P. G.; Muschol, M.; Thomas, B. R.

1996-01-01

Recently. much progress has been made in understanding the nucleation and crystallization of globular proteins, including the formation of compositional and structural crystal defects, Insight into the interactions of (screened) protein macro-ions in solution, obtained from light scattering, small angle X-ray scattering and osmotic pressure studies. can guide the search for crystallization conditions. These studies show that the nucleation of globular proteins is governed by the same principles as that of small molecules. However, failure to account for direct and indirect (hydrodynamic) protein interactions in the solutions results in unrealistic aggregation scenarios. Microscopic studies of numerous proteins reveal that crystals grow by the attachment of growth units through the same layer-spreading mechanisms as inorganic crystals. Investigations of the growth kinetics of hen-egg-white lysozyme (HEWL) reveal non-steady behavior under steady external conditions. Long-term variations in growth rates are due to changes in step-originating dislocation groups. Fluctuations on a shorter timescale reflect the non-linear dynamics of layer growth that results from the interplay between interfacial kinetics and bulk transport. Systematic gel electrophoretic analyses suggest that most HEWL crystallization studies have been performed with material containing other proteins at percent levels. Yet, sub-percent levels of protein impurities impede growth step propagation and play a role in the formation of structural/compositional inhomogeneities. In crystal growth from highly purified HEWL solutions, however, such inhomogeneities are much weaker and form only in response to unusually large changes in growth conditions. Equally important for connecting growth conditions to crystal perfection and diffraction resolution are recent advances in structural characterization through high-resolution Bragg reflection profiling and X-ray topography.

Analyzing multistep homogeneous nucleation in vapor-to-solid transitions using molecular dynamics simulations

NASA Astrophysics Data System (ADS)

Tanaka, Kyoko K.; Diemand, Jürg; Tanaka, Hidekazu; Angélil, Raymond

2017-08-01

In this paper, we present multistep homogeneous nucleations in vapor-to-solid transitions as revealed by molecular dynamics simulations on Lennard-Jones molecules, where liquidlike clusters are created and crystallized. During a long, direct N V E (constant volume, energy, and number of molecules) involving the integration of (1.9 -15 )× 106 molecules in up to 200 million steps (=4.3 μ s ), crystallization in many large, supercooled nanoclusters is observed once the liquid clusters grow to a certain size (˜800 molecules for the case of T ≃0.5 ɛ /k ). In the simulations, we discovered an interesting process associated with crystallization: the solid clusters lost 2-5 % of their mass during crystallization at low temperatures below their melting temperatures. Although the crystallized clusters were heated by latent heat, they were stabilized by cooling due to evaporation. The clusters crystallized quickly and completely except at surface layers. However, they did not have stable crystal structures, rather they had metastable structures such as icosahedral, decahedral, face-centered-cubic-rich (fcc-rich), and hexagonal-close-packed-rich (hcp-rich). Several kinds of cluster structures coexisted in the same size range of ˜1000 -5000 molecules. Our results imply that multistep nucleation is a common first stage of condensation from vapor to solid.

Crystallization and preliminary X-ray crystallographic analysis of the small subunit of the heterodimeric laccase POXA3b from Pleurotus ostreatus

PubMed Central

Ferraroni, Marta; Scozzafava, Andrea; Ullah, Sana; Tron, Thierry; Piscitelli, Alessandra; Sannia, Giovanni

2014-01-01

Laccases are multicopper oxidases of great biotechnological potential. While laccases are generally monomeric glycoproteins, the white-rot fungus Pleurotus ostreatus produces two closely related heterodimeric isoenzymes composed of a large subunit, homologous to the other fungal laccases, and a small subunit. The sequence of the small subunit does not show significant homology to any other protein or domain of known function and consequently its function is unknown. The highest similarity to proteins of known structure is to a putative enoyl-CoA hydratase/isomerase from Acinetobacter baumannii, which shows an identity of 27.8%. Diffraction-quality crystals of the small subunit of the heterodimeric laccase POXA3b (sPOXA3b) from P. ostreatus were obtained using the sitting-drop vapour-diffusion method at 294 K from a solution consisting of 1.8 M sodium formate, 0.1 M Tris–HCl pH 8.5. The crystals belonged to the tetragonal space group P41212 or P43212, with unit-cell parameters a = 126.6, c = 53.9 Å. The asymmetric unit contains two molecules related by a noncrystallographic twofold axis. A complete data set extending to a maximum resolution of 2.5 Å was collected at 100 K using a wavelength of 1.140 Å. PMID:24419623

New Directions in Biotechnology

NASA Technical Reports Server (NTRS)

2003-01-01

The macromolecule crystallization program within NASA is undergoing considerable pressure, particularly budgetary pressure. While it has shown some successes, they have not lived up to the expectations of others, and technological advances may rapidly overtake the natural advantages offered by crystallization in microgravity. Concomitant with the microgravity effort has been a research program to study the macromolecule crystallization process. It was believed that a better understanding of the process would lead to growth of improved crystals for X-ray diffraction studies. The results of the various research efforts have been impressive in improving our understanding of macromolecule crystallization, but have not led to any improved structures. Macromolecule crystallization for structure determination is "one of", the job being unique for every protein and finished once a structure is obtained. However, the knowledge gained is not lost, but instead lays the foundation for developments in new areas of biotechnology and nanotechnology. In this it is highly analogous to studies into small molecule crystallization, the results of which have led to our present day microelectronics-based society. We are conducting preliminary experiments into areas such as designed macromolecule crystals, macromolecule-inorganic hybrid structures, and macromolecule-based nanotechnology. In addition, our protein crystallization studies are now being directed more towards industrial and new approaches to membrane protein crystallization.

Aqueous alkali halide solutions: can osmotic coefficients be explained on the basis of the ionic sizes alone?

PubMed

Kalyuzhnyi, Yu V; Vlachy, Vojko; Dill, Ken A

2010-06-21

We use the AMSA, associative mean spherical theory of associative fluids, to study ion-ion interactions in explicit water. We model water molecules as hard spheres with four off-center square-well sites and ions as charged hard spheres with sticky sites that bind to water molecules or other ions. We consider alkali halide salts. The choice of model parameters is based on two premises: (i) The strength of the interaction between a monovalent ion and a water molecule is inversely proportional to the ionic (crystal) diameter sigma(i). Smaller ions bind to water more strongly than larger ions do, taking into account the asymmetry of the cation-water and anion-water interactions. (ii) The number of contacts an ion can make is proportional to sigma2(i). In short, small ions bind waters strongly, but only a few of them. Large ions bind waters weakly, but many of them. When both a monovalent cation and anion are large, it yields a small osmotic coefficient of the salt, since the water molecules avoid the space in between large ions. On the other hand, salts formed from one small and one large ion remain hydrated and their osmotic coefficient is high. The osmotic coefficients, calculated using this model in combination with the integral equation theory developed for associative fluids, follow the experimental trends, including the unusual behavior of caesium salts.

Structure of the myotonic dystrophy type 2 RNA and designed small molecules that reduce toxicity.

PubMed

Childs-Disney, Jessica L; Yildirim, Ilyas; Park, HaJeung; Lohman, Jeremy R; Guan, Lirui; Tran, Tuan; Sarkar, Partha; Schatz, George C; Disney, Matthew D

2014-02-21

Myotonic dystrophy type 2 (DM2) is an incurable neuromuscular disorder caused by a r(CCUG) expansion (r(CCUG)(exp)) that folds into an extended hairpin with periodically repeating 2×2 nucleotide internal loops (5'CCUG/3'GUCC). We designed multivalent compounds that improve DM2-associated defects using information about RNA-small molecule interactions. We also report the first crystal structure of r(CCUG) repeats refined to 2.35 Å. Structural analysis of the three 5'CCUG/3'GUCC repeat internal loops (L) reveals that the CU pairs in L1 are each stabilized by one hydrogen bond and a water-mediated hydrogen bond, while CU pairs in L2 and L3 are stabilized by two hydrogen bonds. Molecular dynamics (MD) simulations reveal that the CU pairs are dynamic and stabilized by Na(+) and water molecules. MD simulations of the binding of the small molecule to r(CCUG) repeats reveal that the lowest free energy binding mode occurs via the major groove, in which one C residue is unstacked and the cross-strand nucleotides are displaced. Moreover, we modeled the binding of our dimeric compound to two 5'CCUG/3'GUCC motifs, which shows that the scaffold on which the RNA-binding modules are displayed provides an optimal distance to span two adjacent loops.

Structure of the Myotonic Dystrophy Type 2 RNA and Designed Small Molecules That Reduce Toxicity

PubMed Central

Park, HaJeung; Lohman, Jeremy R.; Guan, Lirui; Tran, Tuan; Sarkar, Partha; Schatz, George C.; Disney, Matthew D.

2014-01-01

Myotonic dystrophy type 2 (DM2) is an untreatable neuromuscular disorder caused by a r(CCUG) expansion (r(CCUG)exp) that folds into an extended hairpin with periodically repeating 2×2 nucleotide internal loops (5’CCUG/3’GUCC). We designed multivalent compounds that improve DM2-associated defects using information about RNA-small molecule interactions. We also report the first crystal structure of r(CCUG)exp refined to 2.35 Å. Structural analysis of the three 5’CCUG/3’GUCC repeat internal loops (L) reveals that the CU pairs in L1 are each stabilized by one hydrogen bond and a water-mediated hydrogen bond while CU pairs in L2 and L3 are stabilized by two hydrogen bonds. Molecular dynamics (MD) simulations reveal that the CU pairs are dynamic and stabilized by Na+ and water molecules. MD simulations of the binding of the small molecule to r(CCUG) repeats reveal that the lowest free energy binding mode occurs via the major groove, in which one C residue is unstacked and the cross-strand nucleotides are displaced. Moreover, we modeled the binding of our dimeric compound to two 5’CCUG/3’GUCC motifs, which shows that the scaffold on which the RNA-binding modules are displayed provides an optimal distance to span two adjacent loops. PMID:24341895

Crystallography Open Database (COD): an open-access collection of crystal structures and platform for world-wide collaboration

PubMed Central

Gražulis, Saulius; Daškevič, Adriana; Merkys, Andrius; Chateigner, Daniel; Lutterotti, Luca; Quirós, Miguel; Serebryanaya, Nadezhda R.; Moeck, Peter; Downs, Robert T.; Le Bail, Armel

2012-01-01

Using an open-access distribution model, the Crystallography Open Database (COD, http://www.crystallography.net) collects all known ‘small molecule / small to medium sized unit cell’ crystal structures and makes them available freely on the Internet. As of today, the COD has aggregated ∼150 000 structures, offering basic search capabilities and the possibility to download the whole database, or parts thereof using a variety of standard open communication protocols. A newly developed website provides capabilities for all registered users to deposit published and so far unpublished structures as personal communications or pre-publication depositions. Such a setup enables extension of the COD database by many users simultaneously. This increases the possibilities for growth of the COD database, and is the first step towards establishing a world wide Internet-based collaborative platform dedicated to the collection and curation of structural knowledge. PMID:22070882

Crystal structure of Streptococcus pneumoniae pneumolysin provides key insights into early steps of pore formation

PubMed Central

Lawrence, Sara L.; Feil, Susanne C.; Morton, Craig J.; Farrand, Allison J.; Mulhern, Terrence D.; Gorman, Michael A.; Wade, Kristin R.; Tweten, Rodney K.; Parker, Michael W.

2015-01-01

Pore-forming proteins are weapons often used by bacterial pathogens to breach the membrane barrier of target cells. Despite their critical role in infection important structural aspects of the mechanism of how these proteins assemble into pores remain unknown. Streptococcus pneumoniae is the world’s leading cause of pneumonia, meningitis, bacteremia and otitis media. Pneumolysin (PLY) is a major virulence factor of S. pneumoniae and a target for both small molecule drug development and vaccines. PLY is a member of the cholesterol-dependent cytolysins (CDCs), a family of pore-forming toxins that form gigantic pores in cell membranes. Here we present the structure of PLY determined by X-ray crystallography and, in solution, by small-angle X-ray scattering. The crystal structure reveals PLY assembles as a linear oligomer that provides key structural insights into the poorly understood early monomer-monomer interactions of CDCs at the membrane surface. PMID:26403197

Exploration of multiple Sortase A protein conformations in virtual screening

NASA Astrophysics Data System (ADS)

Gao, Chunxia; Uzelac, Ivana; Gottfries, Johan; Eriksson, Leif A.

2016-02-01

Methicillin resistant Staphylococcus aureus (MRSA) has become a major health concern which has brought about an urgent need for new therapeutic agents. As the S. aureus Sortase A (SrtA) enzyme contributes to the adherence of the bacteria to the host cells, inhibition thereof by small molecules could be employed as potential antivirulence agents, also towards resistant strains. Albeit several virtual docking SrtA campaigns have been reported, no strongly inhibitatory non-covalent binders have as yet emerged therefrom. In order to better understand the binding modes of small molecules, and the effect of different receptor structures employed in the screening, we herein report on an exploratory study employing 10 known binders and 500 decoys on 100 SrtA structures generated from regular or steered molecular dynamics simulations on four different SrtA crystal/NMR structures. The results suggest a correlation between the protein structural flexibility and the virtual screening performance, and confirm the noted immobilization of the β6/β7 loop upon substrate binding. The NMR structures reported appear to perform slightly better than the Xray-crystal structures, but the binding modes fluctuate tremendously, and it might be suspected that the catalytic site is not necessarily the preferred site of binding for some of the reported active compounds.

Structure of a small-molecule inhibitor complexed with GlmU from Haemophilus influenzae reveals an allosteric binding site

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mochalkin, Igor; Lightle, Sandra; Narasimhan, Lakshmi

2008-04-02

N-Acetylglucosamine-1-phosphate uridyltransferase (GlmU) is an essential enzyme in aminosugars metabolism and an attractive target for antibiotic drug discovery. GlmU catalyzes the formation of uridine-diphospho-N-acetylglucosamine (UDP-GlcNAc), an important precursor in the peptidoglycan and lipopolisaccharide biosynthesis in both Gram-negative and Gram-positive bacteria. Here we disclose a 1.9 {angstrom} resolution crystal structure of a synthetic small-molecule inhibitor of GlmU from Haemophilus influenzae (hiGlmU). The compound was identified through a high-throughput screening (HTS) configured to detect inhibitors that target the uridyltransferase active site of hiGlmU. The original HTS hit exhibited a modest micromolar potency (IC{sub 50} - 18 {mu}M in a racemic mixture) againstmore » hiGlmU and no activity against Staphylococcus aureus GlmU (saGlmU). The determined crystal structure indicated that the inhibitor occupies an allosteric site adjacent to the GlcNAc-1-P substrate-binding region. Analysis of the mechanistic model of the uridyltransferase reaction suggests that the binding of this allosteric inhibitor prevents structural rearrangements that are required for the enzymatic reaction, thus providing a basis for structure-guided design of a new class of mechanism-based inhibitors of GlmU.« less

Exploration of multiple Sortase A protein conformations in virtual screening

PubMed Central

Gao, Chunxia; Uzelac, Ivana; Gottfries, Johan; Eriksson, Leif A.

2016-01-01

Methicillin resistant Staphylococcus aureus (MRSA) has become a major health concern which has brought about an urgent need for new therapeutic agents. As the S. aureus Sortase A (SrtA) enzyme contributes to the adherence of the bacteria to the host cells, inhibition thereof by small molecules could be employed as potential antivirulence agents, also towards resistant strains. Albeit several virtual docking SrtA campaigns have been reported, no strongly inhibitatory non-covalent binders have as yet emerged therefrom. In order to better understand the binding modes of small molecules, and the effect of different receptor structures employed in the screening, we herein report on an exploratory study employing 10 known binders and 500 decoys on 100 SrtA structures generated from regular or steered molecular dynamics simulations on four different SrtA crystal/NMR structures. The results suggest a correlation between the protein structural flexibility and the virtual screening performance, and confirm the noted immobilization of the β6/β7 loop upon substrate binding. The NMR structures reported appear to perform slightly better than the Xray-crystal structures, but the binding modes fluctuate tremendously, and it might be suspected that the catalytic site is not necessarily the preferred site of binding for some of the reported active compounds. PMID:26846342

Manipulating explosive sensitivity through structural modifications in a nitrate ester system

NASA Astrophysics Data System (ADS)

Manner, Virginia

2017-06-01

Understanding how condensed phase effects influence sensitivity is essential for developing next generation insensitive high explosives. However, the ability to predictably manipulate explosive sensitivity remains an elusive goal. Explosive sensitivity has been suggested to be governed by multiple factors, from intramolecular effects such as bond dissociation energy, oxygen balance, and the electrostatic potential of reactive functional groups, to larger scale effects, such as crystal structure and hot spot formation. We have developed derivatives of the explosive pentaerythritol tetranitrate (PETN) and examined them experimentally and theoretically, in order to better understand which properties influence sensitivity. With this molecular framework, we can evaluate how small changes to the structure of the molecule influence qualities such as oxygen balance, heat of formation, heat capacity, compressibility, crystal packing, and hydrogen bonding, through techniques such as differential scanning calorimetry, x-ray crystallography, and atomistic simulation. We have also used small-scale sensitivity testing as an initial tool to screen for large and consistent differences in handling sensitivity. We will discuss the many factors that contribute to sensitivity in this series of systematically-modified molecules as well as in existing well-studied explosive systems, such as triaminotrinitrobenzene (TATB) and nitroglycerin (NG). In collaboration with: Thomas Myers, Marc Cawkwell, Edward Kober, Bryce Tappan, Geoffrey Brown, Mary Sandstrom, LOS ALAMOS NATL LAB.

The HD molecule in small and medium cages of clathrate hydrates: Quantum dynamics studied by neutron scattering measurements and computation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Colognesi, Daniele; Celli, Milva; Ulivi, Lorenzo, E-mail: lorenzo.ulivi@isc.cnr.it

2014-10-07

We report inelastic neutron scattering (INS) measurements on molecular hydrogen deuteride (HD) trapped in binary cubic (sII) and hexagonal (sH) clathrate hydrates, performed at low temperature using two different neutron spectrometers in order to probe both energy and momentum transfer. The INS spectra of binary clathrate samples exhibit a rich structure containing sharp bands arising from both the rotational transitions and the rattling modes of the guest molecule. For the clathrates with sII structure, there is a very good agreement with the rigorous fully quantum simulations which account for the subtle effects of the anisotropy, angular and radial, of themore » host cage on the HD microscopic dynamics. The sH clathrate sample presents a much greater challenge, due to the uncertainties regarding the crystal structure, which is known only for similar crystals with different promoter, but nor for HD (or H{sub 2}) plus methyl tert-butyl ether (MTBE-d12)« less

Plasmonic nanoparticles-decorated diatomite biosilica: extending the horizon of on-chip chromatography and label-free biosensing.

PubMed

Kong, Xianming; Li, Erwen; Squire, Kenny; Liu, Ye; Wu, Bo; Cheng, Li-Jing; Wang, Alan X

2017-11-01

Diatomite consists of fossilized remains of ancient diatoms and is a type of naturally abundant photonic crystal biosilica with multiple unique physical and chemical functionalities. In this paper, we explored the fluidic properties of diatomite as the matrix for on-chip chromatography and, simultaneously, the photonic crystal effects to enhance the plasmonic resonances of metallic nanoparticles for surface-enhanced Raman scattering (SERS) biosensing. The plasmonic nanoparticle-decorated diatomite biosilica provides a lab-on-a-chip capability to separate and detect small molecules from mixture samples with ultra-high detection sensitivity down to 1 ppm. We demonstrate the significant potential for biomedical applications by screening toxins in real biofluid, achieving simultaneous label-free biosensing of phenethylamine and miR21cDNA in human plasma with unprecedented sensitivity and specificity. To the best of our knowledge, this is the first time demonstration to detect target molecules from real biofluids by on-chip chromatography-SERS techniques. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Thin Film Mediated Phase Change Phenomena: Crystallization, Evaporation and Wetting

NASA Technical Reports Server (NTRS)

Wettlaufer, John S.

1998-01-01

We focus on two distinct materials science problems that arise in two distinct microgravity environments: In space and within the space of a polymeric network. In the former environment, we consider a near eutectic alloy film in contact with its vapor which, when evaporating on earth, will experience compositionally induced buoyancy driven convection. The latter will significantly influence the morphology of the crystallized end member. In the absence of gravity, the morphology will be dominated by molecular diffusion and Marangoni driven viscous flow, and we study these phenomena theoretically and experimentally. The second microgravity environment exists in liquids, gels, and other soft materials where the small mass of individual molecules makes the effect of gravity negligible next to the relatively strong forces of intermolecular collisions. In such materials, an essential question concerns how to relate the molecular dynamics to the bulk rheological behavior. Here, we observe experimentally the diffusive motion of a single molecule in a single polymer filament, embedded within a polymer network and find anomalous diffusive behavior.

Molecular Dynamics Studies of Self-Assembling Biomolecules and DNA-functionalized Gold Nanoparticles

NASA Astrophysics Data System (ADS)

Cho, Vince Y.

This thesis is organized as following. In Chapter 2, we use fully atomistic MD simulations to study the conformation of DNA molecules that link gold nanoparticles to form nanoparticle superlattice crystals. In Chapter 3, we study the self-assembly of peptide amphiphiles (PAs) into a cylindrical micelle fiber by using CGMD simulations. Compared to fully atomistic MD simulations, CGMD simulations prove to be computationally cost-efficient and reasonably accurate for exploring self-assembly, and are used in all subsequent chapters. In Chapter 4, we apply CGMD methods to study the self-assembly of small molecule-DNA hybrid (SMDH) building blocks into well-defined cage-like dimers, and reveal the role of kinetics and thermodynamics in this process. In Chapter 5, we extend the CGMD model for this system and find that the assembly of SMDHs can be fine-tuned by changing parameters. In Chapter 6, we explore superlattice crystal structures of DNA-functionalized gold nanoparticles (DNA-AuNP) with the CGMD model and compare the hybridization.

Crystallization of Stretched Polyimides: A Structure-Property Study

NASA Technical Reports Server (NTRS)

Hinkley, Jeffrey A.; Dezern, James F.

2002-01-01

A simple rotational isomeric state model was used to detect the degree to which polyimide repeat units might align to give an extended crystal. It was found experimentally that the hallmarks of stretch-crystallization were more likely to occur in materials whose molecules could readily give extended, aligned conformations. A proposed screening criterion was 84% accurate in selecting crystallizing molecules.

Racemic & quasi-racemic protein crystallography enabled by chemical protein synthesis.

PubMed

Kent, Stephen Bh

2018-04-04

A racemic protein mixture can be used to form centrosymmetric crystals for structure determination by X-ray diffraction. Both the unnatural d-protein and the corresponding natural l-protein are made by total chemical synthesis based on native chemical ligation-chemoselective condensation of unprotected synthetic peptide segments. Racemic protein crystallography is important for structure determination of the many natural protein molecules that are refractory to crystallization. Racemic mixtures facilitate the crystallization of recalcitrant proteins, and give diffraction-quality crystals. Quasi-racemic crystallization, using a single d-protein molecule, can facilitate the determination of the structures of a series of l-protein analog molecules. Copyright © 2018 Elsevier Ltd. All rights reserved.

Crystal Structure of Mycobacterium tuberculosis H37Rv AldR (Rv2779c), a Regulator of the ald Gene

PubMed Central

Dey, Abhishek; Shree, Sonal; Pandey, Sarvesh Kumar; Tripathi, Rama Pati; Ramachandran, Ravishankar

2016-01-01

Here we report the crystal structure of M. tuberculosis AldR (Rv2779c) showing that the N-terminal DNA-binding domains are swapped, forming a dimer, and four dimers are assembled into an octamer through crystal symmetry. The C-terminal domain is involved in oligomeric interactions that stabilize the oligomer, and it contains the effector-binding sites. The latter sites are 30–60% larger compared with homologs like MtbFFRP (Rv3291c) and can consequently accommodate larger molecules. MtbAldR binds to the region upstream to the ald gene that is highly up-regulated in nutrient-starved tuberculosis models and codes for l-alanine dehydrogenase (MtbAld; Rv2780). Further, the MtbAldR-DNA complex is inhibited upon binding of Ala, Tyr, Trp and Asp to the protein. Studies involving a ligand-binding site G131T mutant show that the mutant forms a DNA complex that cannot be inhibited by adding the amino acids. Comparative studies suggest that binding of the amino acids changes the relative spatial disposition of the DNA-binding domains and thereby disrupt the protein-DNA complex. Finally, we identified small molecules, including a tetrahydroquinoline carbonitrile derivative (S010-0261), that inhibit the MtbAldR-DNA complex. The latter molecules represent the very first inhibitors of a feast/famine regulatory protein from any source and set the stage for exploring MtbAldR as a potential anti-tuberculosis target. PMID:27006398

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kuz'mina, L. G., E-mail: kuzmina@igic.ras.ru; Kucherepa, N. S.; Syrbu, S. A.

The crystal and molecular structure of p-(decaoxybenzylidene)-p'-toluidine C{sub 10}H{sub 21}O-C{sub 6}H{sub 4}-CH=N-C{sub 6}H{sub 4}-CH{sub 3} is studied. The molecule is nearly planar. In the crystal packing, loose regions formed by aliphatic fragments of molecules alternate with pseudostacks of aromatic fragments of molecules that are related by the centers of symmetry. The stacks are built of dimers, in which molecules are linked by {pi}-stacking interactions between benzene rings. There are no weak directional interactions between dimers in a stack. The presence of a single structure-forming element in the crystal, namely, the {pi}-stacking interactions in the dimers, along with the similarity ofmore » the crystal packing to that of the C{sub 8}H{sub 17}O-homologue, which forms a nematic mesophase on melting, indicate that the crystals under study should exhibit nematic properties.« less

Noninvasive in situ observation of the crystallization kinetics of biological macromolecules by confocal laser scanning microscopy.

PubMed

Mühlig, P; Klupsch, Th; Kaulmann, U; Hilgenfeld, R

2003-04-01

High-resolution confocal laser scanning microscopy (CLSM) is a powerful tool for in situ observation and analysis of protein crystal growth kinetics. Because the resolution of CLSM is not diffraction-limited by the object, it is possible to visualize, under certain conditions, objects in molecular dimensions. A modified batch technique is applied which allows the growth kinetics of sufficiently small crystallites fixed at the lower side of a cover glass, within a hanging drop, to be studied in reflected light near the total reflection angle. A gap, or cavity, filled with solution is formed between the cover glass and the upper crystal face, which acts to fix small crystallites by hydrodynamic friction forces. The cavity height enables the propagation of molecular steps across the upper crystal face without constraint, so that the propagation velocity and geometrical parameters can be measured by CLSM. The layer growth kinetics of monoclinic crystallites of a long-acting insulin derivative (Insulin Glargine) is investigated. For a twofold supersaturation of the solution, the growth is governed by 2D nucleation at the edges of the crystallites followed by a spreading of molecular steps. The layer growth kinetics are well fitted by the simple cubic kinetic lattice model. We find that only about one of a thousand solute (protein) molecules which push a kink place due to their Brownian motion becomes really incorporated into the growing crystal.

Fast Rotational Diffusion of Water Molecules in a 2D Hydrogen Bond Network at Cryogenic Temperatures

NASA Astrophysics Data System (ADS)

Prisk, T. R.; Hoffmann, C.; Kolesnikov, A. I.; Mamontov, E.; Podlesnyak, A. A.; Wang, X.; Kent, P. R. C.; Anovitz, L. M.

2018-05-01

Individual water molecules or small clusters of water molecules contained within microporous minerals present an extreme case of confinement where the local structure of hydrogen bond networks are dramatically altered from bulk water. In the zinc silicate hemimorphite, the water molecules form a two-dimensional hydrogen bond network with hydroxyl groups in the crystal framework. Here, we present a combined experimental and theoretical study of the structure and dynamics of water molecules within this network. The water molecules undergo a continuous phase transition in their orientational configuration analogous to a two-dimensional Ising model. The incoherent dynamic structure factor reveals two thermally activated relaxation processes, one on a subpicosecond timescale and another on a 10-100 ps timescale, between 70 and 130 K. The slow process is an in-plane reorientation of the water molecule involving the breaking of hydrogen bonds with a framework that, despite the low temperatures involved, is analogous to rotational diffusion of water molecules in the bulk liquid. The fast process is a localized motion of the water molecule with no apparent analogs among known bulk or confined phases of water.

Fast Rotational Diffusion of Water Molecules in a 2D Hydrogen Bond Network at Cryogenic Temperatures

DOE Office of Scientific and Technical Information (OSTI.GOV)

Prisk, Timothy; Hoffmann, Christina; Kolesnikov, Alexander I.

Individual water molecules or small clusters of water molecules contained within microporous minerals present an extreme case of confinement where the local structure of hydrogen bond networks are dramatically altered from bulk water. In the zinc silicate hemimorphite, the water molecules form a two-dimensional hydrogen bond network with hydroxyl groups in the crystal framework. Here in this paper, we present a combined experimental and theoretical study of the structure and dynamics of water molecules within this network. The water molecules undergo a continuous phase transition in their orientational configuration analogous to a two-dimensional Ising model. The incoherent dynamic structure factormore » reveals two thermally activated relaxation processes, one on a subpicosecond timescale and another on a 10–100 ps timescale, between 70 and 130 K. The slow process is an in-plane reorientation of the water molecule involving the breaking of hydrogen bonds with a framework that, despite the low temperatures involved, is analogous to rotational diffusion of water molecules in the bulk liquid. The fast process is a localized motion of the water molecule with no apparent analogs among known bulk or confined phases of water.« less

Fast Rotational Diffusion of Water Molecules in a 2D Hydrogen Bond Network at Cryogenic Temperatures

DOE PAGES

Prisk, Timothy; Hoffmann, Christina; Kolesnikov, Alexander I.; ...

2018-05-09

Individual water molecules or small clusters of water molecules contained within microporous minerals present an extreme case of confinement where the local structure of hydrogen bond networks are dramatically altered from bulk water. In the zinc silicate hemimorphite, the water molecules form a two-dimensional hydrogen bond network with hydroxyl groups in the crystal framework. Here in this paper, we present a combined experimental and theoretical study of the structure and dynamics of water molecules within this network. The water molecules undergo a continuous phase transition in their orientational configuration analogous to a two-dimensional Ising model. The incoherent dynamic structure factormore » reveals two thermally activated relaxation processes, one on a subpicosecond timescale and another on a 10–100 ps timescale, between 70 and 130 K. The slow process is an in-plane reorientation of the water molecule involving the breaking of hydrogen bonds with a framework that, despite the low temperatures involved, is analogous to rotational diffusion of water molecules in the bulk liquid. The fast process is a localized motion of the water molecule with no apparent analogs among known bulk or confined phases of water.« less

Frequency doubling crystals

DOEpatents

Wang, Francis; Velsko, Stephan P.

1989-01-01

A systematic approach to the production of frequency conversion crystals is described in which a chiral molecule has attached to it a "harmonic generating unit" which contributes to the noncentrosymmetry of the molecule. Certain preferred embodiments of such harmonic generating units include carboxylate, guanadyly and imidazolyl units. Certain preferred crystals include L-arginine fluoride, deuterated L-arginine fluoride, L-arginine chloride monohydrate, L-arginine acetate, dithallium tartrate, ammonium N-acetyl valine, N-acetyl tyrosine and N-acetyl hydroxyproline. Chemical modifications of the chiral molecule, such as deuteration, halogenation and controlled counterion substitution are available to adapt the dispersive properties of a crystal in a particular wavelength region.

Monitoring structural transformations in crystals. 7. 1-Chloroanthracene and its photodimer.

PubMed

Turowska-Tyrk, Ilona; Grześniak, Karolina

2004-02-01

Crystals of the 1-chloroanthracene photodimer, viz. trans-bi(1-chloro-9,10-dihydro-9,10-anthracenediyl), C(28)H(18)Cl(2), were obtained from the solid-state [4+4]-photodimerization of the monomer, C(14)H(9)Cl, followed by recrystallization. The symmetry of the product molecules is defined by the orientation of the reactant molecules in the crystal. The mutual orientation parameters calculated for adjacent monomers explain the reactivity of the compound. The molecules in the crystal of the monomer and the recrystallized photodimer pack differently and the photodimer has crystallographically imposed inversion symmetry.

A universal small molecule, inorganic phosphate, restricts the substrate specificity of Dicer-2 in small RNA biogenesis

PubMed Central

Fukunaga, Ryuya; Zamore, Phillip D

2014-01-01

The enzyme Dicer is central to the production of small silencing RNAs such as microRNAs (miRNAs) and small interfering RNAs (siRNAs). Like other insects, Drosophila melanogaster uses different Dicers to make siRNAs and miRNAs: Dicer-1 produces miRNAs from pre-miRNAs, whereas Dicer-2 generates siRNAs from long double-stranded RNA (dsRNA). How do the 2 Dicers achieve their substrate specificity? Here, we review recent findings that inorganic phosphate restricts the substrate specificity of Dicer-2 to long dsRNA. Inorganic phosphate inhibits Dicer-2 from binding and cleaving pre-miRNAs, without affecting the processing of long dsRNA. Crystal structures of a fragment of human Dicer in complex with an RNA duplex identify a phosphate-binding pocket that recognizes both the 5′-monophosphate of a substrate RNA and inorganic phosphate. We propose that inorganic phosphate occupies the phosphate-binding pocket in the fly Dicer-2, blocking binding of pre-miRNA and restricting pre-miRNA processing to Dicer-1. Thus, a small molecule can alter the substrate specificity of a nucleic acid-processing enzyme. PMID:24787225

Identification of Non-nucleoside Human Ribonucleotide Reductase Modulators

DOE PAGES

Ahmad, Md. Faiz; Huff, Sarah E.; Pink, John; ...

2015-10-21

Ribonucleotide reductase (RR) catalyzes the rate-limiting step of dNTP synthesis and is an established cancer target. Drugs targeting RR are mainly nucleoside in nature. In this study, we sought to identify non-nucleoside small-molecule inhibitors of RR. Using virtual screening, binding affinity, inhibition, and cell toxicity, we have discovered a class of small molecules that alter the equilibrium of inactive hexamers of RR, leading to its inhibition. Several unique chemical categories, including a phthalimide derivative, show micromolar IC 50s and K Ds while demonstrating cytotoxicity. A crystal structure of an active phthalimide binding at the targeted interface supports the noncompetitive modemore » of inhibition determined by kinetic studies. Furthermore, the phthalimide shifts the equilibrium from dimer to hexamer. Finally, together, these data identify several novel non-nucleoside inhibitors of human RR which act by stabilizing the inactive form of the enzyme.« less

On macromolecular refinement at subatomic resolution withinteratomic scatterers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Afonine, Pavel V.; Grosse-Kunstleve, Ralf W.; Adams, Paul D.

2007-11-09

A study of the accurate electron density distribution in molecular crystals at subatomic resolution, better than {approx} 1.0 {angstrom}, requires more detailed models than those based on independent spherical atoms. A tool conventionally used in small-molecule crystallography is the multipolar model. Even at upper resolution limits of 0.8-1.0 {angstrom}, the number of experimental data is insufficient for the full multipolar model refinement. As an alternative, a simpler model composed of conventional independent spherical atoms augmented by additional scatterers to model bonding effects has been proposed. Refinement of these mixed models for several benchmark datasets gave results comparable in quality withmore » results of multipolar refinement and superior of those for conventional models. Applications to several datasets of both small- and macro-molecules are shown. These refinements were performed using the general-purpose macromolecular refinement module phenix.refine of the PHENIX package.« less

On macromolecular refinement at subatomic resolution with interatomic scatterers

PubMed Central

Afonine, Pavel V.; Grosse-Kunstleve, Ralf W.; Adams, Paul D.; Lunin, Vladimir Y.; Urzhumtsev, Alexandre

2007-01-01

A study of the accurate electron-density distribution in molecular crystals at subatomic resolution (better than ∼1.0 Å) requires more detailed models than those based on independent spherical atoms. A tool that is conventionally used in small-molecule crystallography is the multipolar model. Even at upper resolution limits of 0.8–1.0 Å, the number of experimental data is insufficient for full multipolar model refinement. As an alternative, a simpler model composed of conventional independent spherical atoms augmented by additional scatterers to model bonding effects has been proposed. Refinement of these mixed models for several benchmark data sets gave results that were comparable in quality with the results of multipolar refinement and superior to those for conventional models. Applications to several data sets of both small molecules and macromolecules are shown. These refinements were performed using the general-purpose macromolecular refinement module phenix.refine of the PHENIX package. PMID:18007035

On macromolecular refinement at subatomic resolution with interatomic scatterers.

PubMed

Afonine, Pavel V; Grosse-Kunstleve, Ralf W; Adams, Paul D; Lunin, Vladimir Y; Urzhumtsev, Alexandre

2007-11-01

A study of the accurate electron-density distribution in molecular crystals at subatomic resolution (better than approximately 1.0 A) requires more detailed models than those based on independent spherical atoms. A tool that is conventionally used in small-molecule crystallography is the multipolar model. Even at upper resolution limits of 0.8-1.0 A, the number of experimental data is insufficient for full multipolar model refinement. As an alternative, a simpler model composed of conventional independent spherical atoms augmented by additional scatterers to model bonding effects has been proposed. Refinement of these mixed models for several benchmark data sets gave results that were comparable in quality with the results of multipolar refinement and superior to those for conventional models. Applications to several data sets of both small molecules and macromolecules are shown. These refinements were performed using the general-purpose macromolecular refinement module phenix.refine of the PHENIX package.

Exploring the folding pattern of a polymer chain in a single crystal by combining single-molecule force spectroscopy and steered molecular dynamics simulations.

PubMed

Song, Yu; Feng, Wei; Liu, Kai; Yang, Peng; Zhang, Wenke; Zhang, Xi

2013-03-26

Understanding the folding pattern of a single polymer chain within its single crystal will shed light on the mechanism of crystallization. Here, we use the combined techniques of atomic force microscopy (AFM)-based single-molecule force spectroscopy (SMFS) and steered molecular dynamics (SMD) simulations to study the folding pattern of a polyethylene oxide (PEO) chain in its single crystal. Our results show that the folding pattern of a PEO chain in the crystal formed in dilute solution follows the adjacent re-entry folding model. While in the crystal obtained from the melt, the nonadjacent folding with large and irregular loops contributes to big force fluctuations in the force-extension curves. The method established here can offer a novel strategy to directly unravel the chain-folding pattern of polymer single crystals at single-molecule level.

Molecular reorientation of a nematic liquid crystal by thermal expansion

PubMed Central

Kim, Young-Ki; Senyuk, Bohdan; Lavrentovich, Oleg D.

2012-01-01

A unique feature of nematic liquid crystals is orientational order of molecules that can be controlled by electromagnetic fields, surface modifications and pressure gradients. Here we demonstrate a new effect in which the orientation of nematic liquid crystal molecules is altered by thermal expansion. Thermal expansion (or contraction) causes the nematic liquid crystal to flow; the flow imposes a realigning torque on the nematic liquid crystal molecules and the optic axis. The optical and mechanical responses activated by a simple temperature change can be used in sensing, photonics, microfluidic, optofluidic and lab-on-a-chip applications as they do not require externally imposed gradients of temperature, pressure, surface realignment, nor electromagnetic fields. The effect has important ramifications for the current search of the biaxial nematic phase as the optical features of thermally induced structural changes in the uniaxial nematic liquid crystal mimic the features expected of the biaxial nematic liquid crystal. PMID:23072803

Crystal structure of 4,5-dinitro-1 H-imidazole

DOE PAGES

Windler, G. Kenneth; Scott, Brian L.; Tomson, Neil C.; ...

2015-01-01

Here, the title compound, C 3H 2N 4O 4, forms crystals with two molecules in the asymmetric unit which are conformationally similar. With the exception of the O atoms of the nitro groups, the molecules are essentially planar. In the crystal, adjacent molecules are associated by N—H...N hydrogen bonds involving the imidazole N—H donors and N-atom acceptors of the unsaturated nitrogen of neighboring rings, forming layers parallel to (010).

GPU-Accelerated Molecular Dynamics Simulation to Study Liquid Crystal Phase Transition Using Coarse-Grained Gay-Berne Anisotropic Potential.

PubMed

Chen, Wenduo; Zhu, Youliang; Cui, Fengchao; Liu, Lunyang; Sun, Zhaoyan; Chen, Jizhong; Li, Yunqi

2016-01-01

Gay-Berne (GB) potential is regarded as an accurate model in the simulation of anisotropic particles, especially for liquid crystal (LC) mesogens. However, its computational complexity leads to an extremely time-consuming process for large systems. Here, we developed a GPU-accelerated molecular dynamics (MD) simulation with coarse-grained GB potential implemented in GALAMOST package to investigate the LC phase transitions for mesogens in small molecules, main-chain or side-chain polymers. For identical mesogens in three different molecules, on cooling from fully isotropic melts, the small molecules form a single-domain smectic-B phase, while the main-chain LC polymers prefer a single-domain nematic phase as a result of connective restraints in neighboring mesogens. The phase transition of side-chain LC polymers undergoes a two-step process: nucleation of nematic islands and formation of multi-domain nematic texture. The particular behavior originates in the fact that the rotational orientation of the mesogenes is hindered by the polymer backbones. Both the global distribution and the local orientation of mesogens are critical for the phase transition of anisotropic particles. Furthermore, compared with the MD simulation in LAMMPS, our GPU-accelerated code is about 4 times faster than the GPU version of LAMMPS and at least 200 times faster than the CPU version of LAMMPS. This study clearly shows that GPU-accelerated MD simulation with GB potential in GALAMOST can efficiently handle systems with anisotropic particles and interactions, and accurately explore phase differences originated from molecular structures.

GPU-Accelerated Molecular Dynamics Simulation to Study Liquid Crystal Phase Transition Using Coarse-Grained Gay-Berne Anisotropic Potential

PubMed Central

Cui, Fengchao; Liu, Lunyang; Sun, Zhaoyan; Chen, Jizhong; Li, Yunqi

2016-01-01

Gay-Berne (GB) potential is regarded as an accurate model in the simulation of anisotropic particles, especially for liquid crystal (LC) mesogens. However, its computational complexity leads to an extremely time-consuming process for large systems. Here, we developed a GPU-accelerated molecular dynamics (MD) simulation with coarse-grained GB potential implemented in GALAMOST package to investigate the LC phase transitions for mesogens in small molecules, main-chain or side-chain polymers. For identical mesogens in three different molecules, on cooling from fully isotropic melts, the small molecules form a single-domain smectic-B phase, while the main-chain LC polymers prefer a single-domain nematic phase as a result of connective restraints in neighboring mesogens. The phase transition of side-chain LC polymers undergoes a two-step process: nucleation of nematic islands and formation of multi-domain nematic texture. The particular behavior originates in the fact that the rotational orientation of the mesogenes is hindered by the polymer backbones. Both the global distribution and the local orientation of mesogens are critical for the phase transition of anisotropic particles. Furthermore, compared with the MD simulation in LAMMPS, our GPU-accelerated code is about 4 times faster than the GPU version of LAMMPS and at least 200 times faster than the CPU version of LAMMPS. This study clearly shows that GPU-accelerated MD simulation with GB potential in GALAMOST can efficiently handle systems with anisotropic particles and interactions, and accurately explore phase differences originated from molecular structures. PMID:26986851

Performance and Shock Sensitivity Evaluations of Reduced Sensitivity Explosives

NASA Astrophysics Data System (ADS)

Bowden, Patrick; Tappan, Bryce; Schmitt, Matthew; Lichthardt, Joseph; Hill, Larry

2017-06-01

Making high explosives that possess insensitivity on par with TATB-based plastic bonded explosives (PBXs), while outperforming them, has proven to be a difficult challenge. Many molecules that have challenged TATB have fallen short in either small-scale sensitivity (impact, friction), thermal stability, or possessing a shock sensitivity that is either too high or too low. Recently, an alternative approach to single-molecule-based PBXs has been blending and/or co-crystallizing explosive molecules to address shortcomings of individual components. With this approach in mind, formulations have been prepared containing 1,1-diamino-2,2-dinitroethene (DADNE or FOX-7) or 3,3'-diamino-4,4'-azoxyfurazan (DAAF) with 3-nitro-1,2,4-triazole-5-one (NTO). Detailed characterization of these mixtures has been described in a concurrent study. Here we focus on in depth performance metrics such as cylinder wall expansion and CJ pressure (via free surface velocity) and shock sensitivity, by small-scale gap-testing, were investigated as a function of weight percentages of the components. Results will be contrasted with known insensitive high explosives.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ren, Chunyan; Morohashi, Keita; Plotnikov, Alexander N.

Chromobox homolog 7 (CBX7) plays an important role in gene transcription in a wide array of cellular processes, ranging from stem cell self-renewal and differentiation to tumor progression. CBX7 functions through its N-terminal chromodomain (ChD), which recognizes tri-methylated lysine 27 of histone 3 (H3K27me3), a conserved epigenetic mark that signifies gene transcriptional repression. Here in this study, we report discovery of small molecules that inhibit CBX7ChD binding to H3K27me3. Our crystal structures reveal the binding modes of these molecules that compete against H3K27me3 binding through interactions with key residues in the methyl-lysine binding pocket of CBX7ChD. We further show thatmore » a lead compound MS37452, derepresses transcription of Polycomb repressive complex target gene p16/CDKN2A by displacing CBX7 binding to the INK4A/ARF locus in prostate cancer cells. Ultimately, these small molecules have the potential to be developed into high-potency chemical modulators that target CBX7 functions in gene transcription in different disease pathways.« less

Crystal structure of a 2:1 piroxicam–gentisic acid co-crystal featuring neutral and zwitterionic piroxicam molecules

DOE Office of Scientific and Technical Information (OSTI.GOV)

Horstman, Elizabeth M.; Bertke, Jeffery A.; Woods, Toby J.

2016-11-04

A new 2:1 co-crystal of piroxicam and gentisic acid [systematic name: 4-hydroxy-1,1-dioxo-N-(pyridin-2-yl)-2H-1λ 6,2-benzothiazine-3-carboxamide–2-(4-oxido-1,1-dioxo-2H-1λ 6,2-benzothiazine-3-amido)pyridin-1-ium–2,5-dihydroxybenzoic acid, 2C 15H 13N 3O 4S·C 7H 6O 4] has been synthesized using a microfluidic platform and initially identified using Raman spectroscopy. In the co-crystal, one piroxicam molecule is in its neutral form and an intramolecular O—H...O hydrogen bond is observed. The other piroxicam molecule is zwitterionic (proton transfer from the OH group to the pyridine N atom) and two intramolecular N—H...O hydrogen bonds occur. The gentisic acid molecule shows whole-molecule disorder over two sets of sites in a 0.809(2):0.191(2) ratio. In the crystal, extensive hydrogenmore » bonding between the components forms layers propagating in theabplane.« less

Crystal structure of tetra-kis-(μ3-2-{[1,1-bis-(hy-droxy-meth-yl)-2-oxidoeth-yl]imino-meth-yl}-6-meth-oxy-phenolato)tetra-kis-[aqua-copper(II)]: a redetermination at 200 K.

PubMed

Buvaylo, Elena A; Vassilyeva, Olga Yu; Skelton, Brian W

2015-10-01

The crystal structure of the tetra-nuclear title compound, [Cu4(C12H15NO5)4(H2O)4], has been previously reported by Back, Oliveira, Canabarro & Iglesias [Z. Anorg. Allg. Chem. (2015), 641, 941-947], based on room-temperature data. In the previously published structure, no standard uncertainties are recorded for the deprotonated hy-droxy-methyl group and water mol-ecule O atoms coordinating to the metal atom indicating that they were not refined; furthermore, the H atoms of some OH groups and water mol-ecules have not been positioned accurately. Since the current structure was determined at a lower temperature, all atoms, including the H atoms of these hy-droxy groups and the water mol-ecule, have been determined more accurately resulting in improved standard uncertainties in the bond lengths and angles. Diffraction data were collected at 200 K, rather than the more usual 100 K, due to apparent disordering at lower temperatures. In addition, it is now possible to report intra- and inter-molecular O-H⋯O inter-actions. In the title complex molecule, which has crystallographic -4 symmetry, the Cu(II) ions are coordinated by the tridentate Schiff base ligands and water mol-ecules, forming a tetra-nuclear Cu4O4 cubane-like core. The Cu(II) ion adopts a CuNO5 elongated octa-hedral environment. The coordination environment of Cu(II) at 200 K displays a small contraction of the Cu-N/O bonds, compared with the room-temperature structure. In the crystal lattice, the neutral clusters are linked by inter-molecular O-H⋯O hydrogen bonds into a one-dimensional hydrogen-bonding network propagating along the b axis.

DHS Internship Summary-Crystal Assembly at Different Length Scales

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mishchenko, L

2009-08-06

I was part of a project in which in situ atomic force microscopy (AFM) was used to monitor growth and dissolution of atomic and colloidal crystals. At both length scales, the chemical environment of the system greatly altered crystal growth and dissolution. Calcium phosphate was used as a model system for atomic crystals. A dissolution-reprecipitation reaction was observed in this first system, involving the conversion of brushite (DCPD) to octacalcium phosphate (OCP). In the second system, polymeric colloidal crystals were dissolved in an ionic solvent, revealing the underlying structure of the crystal. The dissolved crystal was then regrown through anmore » evaporative step method. Recently, we have also found that colloids can be reversibly deposited in situ onto an ITO (indium tin oxide) substrate via an electrochemistry setup. The overall goal of this project was to develop an understanding of the mechanisms that control crystallization and order, so that these might be controlled during material synthesis. Controlled assembly of materials over a range of length scales from molecules to nanoparticles to colloids is critical for designing new materials. In particular, developing materials for sensor applications with tailorable properties and long range order is important. In this work, we examine two of these length scales: small molecule crystallization of calcium phosphate (whose crystal phases include DCPD, OCP, and HAP) and colloidal crystallization of Poly(methyl methacrylate) beads. Atomic Force Microscopy is ideal for this line of work because it allows for the possibility of observing non-conducting samples in fluid during growth with high resolution ({approx} 10 nm). In fact, during atomic crystal growth one can observe changes in atomic steps, and with colloidal crystals, one can monitor the individual building blocks of the crystal. Colloids and atoms crystallize under the influence of different forces acting at different length scales as seen in Table 1. In particular, molecular crystals, which are typically dominated by ionic and covalent bonding, are an order of magnitude more strongly bonded than colloidal crystals. In molecular crystals, ordering is driven by the interaction potentials between molecules. By contrast, colloidal assembly is a competition between the repulsive electrostatic forces that prevent aggregation in solution (due to surface charge), and short-range van der Waals and entropic forces that leads to ordering. Understanding atomic crystallization is fundamentally important for fabrication of tailorable crystalline materials, for example for biological or chemical sensors. The transformation of brushite to OCP not only serves as a model system for atomic crystal growth (applicable to many other crystal growth processes), but is also important in bone cements. Colloidal crystals have unique optical properties which respond to chemical and mechanical stimuli, making them very important for sensing applications. The mechanism of colloidal crystal assembly is thus fundamentally important. Our in situ dissolution and regrowth experiments are one good method of analyzing how these crystals pack under different conditions and how defect sites are formed and filled. In these experiments, a silica additive was used to strengthen the colloidal crystal during initial assembly (ex situ) and to increase domain size and long range order. Reversible electrodeposition of colloids onto a conductive substrate (ITO in our case) is another system which can further our knowledge of colloidal assembly. This experiment holds promise of allowing in situ observation of colloidal crystal growth and the influence of certain additives on crystal order. The ultimate goal would be to achieve long range order in these crystals by changing the surface charge or the growth environment.« less

A potentiometric titration method for the crystallization of drug-like organic molecules.

PubMed

Du-Cuny, Lei; Huwyler, Jörg; Fischer, Holger; Kansy, Manfred

2007-09-05

It is generally accepted, that crystalline solids representing a low energy polymorph should be selected for development of oral dosage forms. As a consequence, efficient and robust procedures are needed at an early stage during drug discovery to prepare crystals from drug-like organic molecules. In contrast to the use of supersaturated solutions, we present a potentiometric crystallization procedure where saturated solutions are prepared in a controlled manner by pH-titration. Crystallization is carried out under defined conditions using the sample concentration and experimental pK(a) values as input parameters. Crystals of high quality were obtained for 11 drugs selected to demonstrate the efficiency and applicability of the new method. Technical improvements are suggested to overcome practical limitations and to enhance the possibility of obtaining crystals from molecules in their uncharged form.

Selectivity by Small-Molecule Inhibitors of Protein Interactions Can Be Driven by Protein Surface Fluctuations

PubMed Central

Johnson, David K.; Karanicolas, John

2015-01-01

Small-molecules that inhibit interactions between specific pairs of proteins have long represented a promising avenue for therapeutic intervention in a variety of settings. Structural studies have shown that in many cases, the inhibitor-bound protein adopts a conformation that is distinct from its unbound and its protein-bound conformations. This plasticity of the protein surface presents a major challenge in predicting which members of a protein family will be inhibited by a given ligand. Here, we use biased simulations of Bcl-2-family proteins to generate ensembles of low-energy conformations that contain surface pockets suitable for small molecule binding. We find that the resulting conformational ensembles include surface pockets that mimic those observed in inhibitor-bound crystal structures. Next, we find that the ensembles generated using different members of this protein family are overlapping but distinct, and that the activity of a given compound against a particular family member (ligand selectivity) can be predicted from whether the corresponding ensemble samples a complementary surface pocket. Finally, we find that each ensemble includes certain surface pockets that are not shared by any other family member: while no inhibitors have yet been identified to take advantage of these pockets, we expect that chemical scaffolds complementing these “distinct” pockets will prove highly selective for their targets. The opportunity to achieve target selectivity within a protein family by exploiting differences in surface fluctuations represents a new paradigm that may facilitate design of family-selective small-molecule inhibitors of protein-protein interactions. PMID:25706586

Crystallography Open Database – an open-access collection of crystal structures

PubMed Central

Gražulis, Saulius; Chateigner, Daniel; Downs, Robert T.; Yokochi, A. F. T.; Quirós, Miguel; Lutterotti, Luca; Manakova, Elena; Butkus, Justas; Moeck, Peter; Le Bail, Armel

2009-01-01

The Crystallography Open Database (COD), which is a project that aims to gather all available inorganic, metal–organic and small organic molecule structural data in one database, is described. The database adopts an open-access model. The COD currently contains ∼80 000 entries in crystallographic information file format, with nearly full coverage of the International Union of Crystallography publications, and is growing in size and quality. PMID:22477773

Pure white OLED based on an organic small molecule: 2,6-Di(1H-benzo[d]imidazol-2-yl)pyridine.

PubMed

Liu, Jian

2015-10-05

2,6-Di(1H-benzo[d]imidazol-2-yl)pyridine (DBIP) was synthesized. The single-crystal structure of DBIP was resolved. DBIP-based OLED was fabricated. The electroluminescence for the device corresponds to a pure white emission. In addition, thermal stability, UV-vis, photoluminescence and electrochemical behaviors of DBIP were investigated as well. Copyright © 2015 Elsevier B.V. All rights reserved.

Microgravity

NASA Image and Video Library

2000-11-15

Watching molecules of the iron-storing protein apoferritin come together to form a nucleus reveals some interesting behavior. In this series of images, researchers observed clusters of four molecules at the corners of a diamond shape (top). As more molecules attach to the cluster, they arrange themselves into rods (second from top), and a raft-like configuration of molecules forms the critical nucleus (third from top), suggesting that crystal growth is much slower than it could be were the molecules arranged in a more compact formation. In the final image, a crystallite consisting of three layers containing approximately 60 to 70 molecules each is formed. Atomic force microscopy made visualizing the process of nucleation possible for the first time. The principal investigator is Peter Vekilov, of the University of Alabama in Huntsville. Vekilov's team at UAH studies protein solutions as they change phases from liquids to crystalline solids. They want to know if the molecules in the solution interact with one another, and if so, how, from the perspectives of thermodynamics and kinetics. They want to understand which forces -- electrical, electrostatic, hydrodynamic, or other kinds of forces -- are responsible for the interactions. They also study nucleation, the begirning stage of crystallization. This process is important to understand because it sets the stage for crystal growth in all kinds of solutions and liquid melts that are important in such diverse fields as agriculture, medicine, and the fabrication of metal components. Nucleation can determine the rate of crystal growth, the number of crystals that will be formed, and the quality and size of the crystals.

The different conformations and crystal structures of dihydroergocristine

NASA Astrophysics Data System (ADS)

Mönch, B.; Kraus, W.; Köppen, R.; Emmerling, F.

2016-02-01

The identification of different forms of dihydroergocristine (DHEC) was carried out by crystallization from different organic solvents. DHEC was identified as potential template for molecularly imprinted polymers (MIPs) for the epimeric specific analysis of ergot alkaloids (EAs) in food. DHEC was crystallized from different solvents in order to mimic the typical MIP synthesis conditions. Four new solvatomorphs of DHEC were obtained. All solvatomorphs contain a water molecule in the crystal structure, whereas three compounds contain an additional solvent molecule. Based on the conformation of DHEC a comparison with typical EA molecules was possible. The analysis showed that DHEC is a suitable template for MIPs for EAs.

Exceptional enhancement of Raman scattering on silver chlorobromide nanocube photonic crystals: chemical and photonic contributions

DOE PAGES

Li, Zheng; Gosztola, David J.; Sun, Cheng-Jun; ...

2015-02-02

Photonic crystals made from self-assembly of mono-dispersed AgCl xBr 1-x nanocubes, which are not plasmonically active, have been discovered to exceptionally enhance Raman scattering of molecules chemically adsorbed on their surfaces. Comprehensive control measurements and X-ray absorption near-edge structure spectroscopy indicate that the Raman enhancement on the AgCl xBr 1-x nanocube photonic crystals is primarily ascribed to the chemical enhancement mechanism associated with the chemical interactions between adsorbing molecules and the AgCl xBr 1-x surfaces. In addition, the ordering of the AgCl xBr 1-x nanocubes in the photonic crystals can selectively reflect Raman scattering back to the detector at themore » bandgap position of the photonic crystals to provide additional enhancement, i.e., photonic mode enhancement. The thiophenol molecules adsorbed on the AgCl 0.44Br 0.56 nanocube photonic crystals exhibit astonishingly strong Raman signals that are on the same order of magnitude as those recorded from the thiophenol molecules adsorbed on the assembled Ag nanocubes.« less

Calculating hyperfine couplings in large ionic crystals containing hundreds of QM atoms: subsystem DFT is the key.

PubMed

Kevorkyants, Ruslan; Wang, Xiqiao; Close, David M; Pavanello, Michele

2013-11-14

We present an application of the linear scaling frozen density embedding (FDE) formulation of subsystem DFT to the calculation of isotropic hyperfine coupling constants (hfcc's) of atoms belonging to a guanine radical cation embedded in a guanine hydrochloride monohydrate crystal. The model systems range from an isolated guanine to a 15,000 atom QM/MM cluster where the QM region is comprised of 36 protonated guanine cations, 36 chlorine anions, and 42 water molecules. Our calculations show that the embedding effects of the surrounding crystal cannot be reproduced by small model systems nor by a pure QM/MM procedure. Instead, a large QM region is needed to fully capture the complicated nature of the embedding effects in this system. The unprecedented system size for a relativistic all-electron isotropic hfcc calculation can be approached in this work because the local nature of the electronic structure of the organic crystals considered is fully captured by the FDE approach.

Solution-printed organic semiconductor blends exhibiting transport properties on par with single crystals

PubMed Central

Niazi, Muhammad R.; Li, Ruipeng; Qiang Li, Er; Kirmani, Ahmad R.; Abdelsamie, Maged; Wang, Qingxiao; Pan, Wenyang; Payne, Marcia M.; Anthony, John E.; Smilgies, Detlef-M.; Thoroddsen, Sigurdur T.; Giannelis, Emmanuel P.; Amassian, Aram

2015-01-01

Solution-printed organic semiconductors have emerged in recent years as promising contenders for roll-to-roll manufacturing of electronic and optoelectronic circuits. The stringent performance requirements for organic thin-film transistors (OTFTs) in terms of carrier mobility, switching speed, turn-on voltage and uniformity over large areas require performance currently achieved by organic single-crystal devices, but these suffer from scale-up challenges. Here we present a new method based on blade coating of a blend of conjugated small molecules and amorphous insulating polymers to produce OTFTs with consistently excellent performance characteristics (carrier mobility as high as 6.7 cm2 V−1 s−1, low threshold voltages of<1 V and low subthreshold swings <0.5 V dec−1). Our findings demonstrate that careful control over phase separation and crystallization can yield solution-printed polycrystalline organic semiconductor films with transport properties and other figures of merit on par with their single-crystal counterparts. PMID:26592862

Solution-printed organic semiconductor blends exhibiting transport properties on par with single crystals.

PubMed

Niazi, Muhammad R; Li, Ruipeng; Qiang Li, Er; Kirmani, Ahmad R; Abdelsamie, Maged; Wang, Qingxiao; Pan, Wenyang; Payne, Marcia M; Anthony, John E; Smilgies, Detlef-M; Thoroddsen, Sigurdur T; Giannelis, Emmanuel P; Amassian, Aram

2015-11-23

Solution-printed organic semiconductors have emerged in recent years as promising contenders for roll-to-roll manufacturing of electronic and optoelectronic circuits. The stringent performance requirements for organic thin-film transistors (OTFTs) in terms of carrier mobility, switching speed, turn-on voltage and uniformity over large areas require performance currently achieved by organic single-crystal devices, but these suffer from scale-up challenges. Here we present a new method based on blade coating of a blend of conjugated small molecules and amorphous insulating polymers to produce OTFTs with consistently excellent performance characteristics (carrier mobility as high as 6.7 cm(2) V(-1) s(-1), low threshold voltages of<1 V and low subthreshold swings <0.5 V dec(-1)). Our findings demonstrate that careful control over phase separation and crystallization can yield solution-printed polycrystalline organic semiconductor films with transport properties and other figures of merit on par with their single-crystal counterparts.

Production and crystallization of recombinant JAK proteins.

PubMed

Lucet, Isabelle S; Bamert, Rebecca

2013-01-01

JAK kinases are critical mediators in development, differentiation, and homeostasis and accordingly, have become well-validated targets for drug discovery efforts. In recent years, the integration of X-ray crystallography in kinase-focused drug discovery programs has provided a powerful rationale for chemical modification by allowing a unique glimpse of a bound inhibitor to its target. Such structural information has not only led to an improved understanding of the key drivers of potency and specificity of several JAK-specific compounds but has greatly facilitated and accelerated the design of compounds with improved pharmacokinetic properties.JAK kinases are traditionally difficult candidates to express in significant quantities, generally requiring eukaryotic expression systems, protein engineering, mutations to yield soluble, homogeneous samples suitable for crystallization studies. Here we review the key methods utilized to express, purify, and crystallize the JAK kinases and provide a detail description of the methods that we have developed to express, purify, and crystallize recombinant JAK1 and JAK2 proteins in the presence of small molecule inhibitors.

Protein crystal growth

NASA Technical Reports Server (NTRS)

2001-01-01

Atomic force microscopy uses laser technology to reveal a defect, a double-screw dislocation, on the surface of this crystal of canavalin, a major source of dietary protein for humans and domestic animals. When a crystal grows, attachment kinetics and transport kinetics are competing for control of the molecules. As a molecule gets close to the crystal surface, it has to attach properly for the crystal to be usable. NASA has funded investigators to look at those attachment kinetics from a theoretical standpoint and an experimental standpoint. Dr. Alex McPherson of the University of California, Irvine, is one of those investigators. He uses X-ray diffraction and atomic force microscopy in his laboratory to answer some of the many questions about how protein crystals grow. Atomic force microscopy provides a means of looking at how individual molecules are added to the surface of growing protein crystals. This helps McPherson understand the kinetics of protein crystal growth. McPherson asks, How fast do crystals grow? What are the forces involved? Investigators funded by NASA have clearly shown that such factors as the level of supersaturation and the rate of growth all affect the habit [characteristic arrangement of facets] of the crystal and the defects that occur in the crystal.

Effect of Aggregation on Squaraine Fullerene Bulk-Heterojunction Organic Photovoltaic Devices

NASA Astrophysics Data System (ADS)

Jalan, Ishita

Organic photovoltaics (OPV) offer great promise as a low-cost renewable energy source, the relative low efficiency still challenges its commercialization potential. Small conjugated molecules like Squaraine (SQ) molecules show promising advancement in organic photovoltaics (OPV). Advantages of SQ over other materials is that it has a high extinction coefficient (>105), decent photo-stability, good synthetic reproducibility, and tunable molecular structure. With small chemical modifications, the squaraines can have substantial impact on photophysical properties and aggregation pattern, and thus on operational OPV efficiency. The squaraine molecule that will be studied in this work is a symmetric aniline-based squaraine with n-hexyl chain on the molecular arm with di hydroxyl substituents on the aniline, this will be referred to DHSQ(OH) 2. In this work, the assignment of the monomer and aggregate peak is discussed. It is known that crystallinity is important for efficient charge transport and exciton diffusion in the BHJ, this thesis focuses on thermal and solvent vapor annealing the as-cast films to reduce the amorphous regions. It is observed that crystallinity is improved but often at the expense of larger crystal size. Therefore, to achieve optimal OPV efficiency, this tradeoff is controlled to improve the crystallinity while maintaining a small, highly mixed BHJ morphology.

Toward Understanding the Outer Membrane Uptake of Small Molecules by Pseudomonas aeruginosa*

PubMed Central

Eren, Elif; Parkin, Jamie; Adelanwa, Ayodele; Cheneke, Belete; Movileanu, Liviu; Khalid, Syma; van den Berg, Bert

2013-01-01

Because small molecules enter Gram-negative bacteria via outer membrane (OM) channels, understanding OM transport is essential for the rational design of improved and new antibiotics. In the human pathogen Pseudomonas aeruginosa, most small molecules are taken up by outer membrane carboxylate channel (Occ) proteins, which can be divided into two distinct subfamilies, OccD and OccK. Here we characterize substrate transport mediated by Occ proteins belonging to both subfamilies. Based on the determination of the OccK2-glucuronate co-crystal structure, we identify the channel residues that are essential for substrate transport. We further show that the pore regions of the channels are rigid in the OccK subfamily and highly dynamic in the OccD subfamily. We also demonstrate that the substrate carboxylate group interacts with central residues of the basic ladder, a row of arginine and lysine residues that leads to and away from the binding site at the channel constriction. Moreover, the importance of the basic ladder residues corresponds to their degree of conservation. Finally, we apply the generated insights by converting the archetype of the entire family, OccD1, from a basic amino acid-specific channel into a channel with a preference for negatively charged amino acids. PMID:23467408

Organic field-effect transistors using single crystals.

PubMed

Hasegawa, Tatsuo; Takeya, Jun

2009-04-01

Organic field-effect transistors using small-molecule organic single crystals are developed to investigate fundamental aspects of organic thin-film transistors that have been widely studied for possible future markets for 'plastic electronics'. In reviewing the physics and chemistry of single-crystal organic field-effect transistors (SC-OFETs), the nature of intrinsic charge dynamics is elucidated for the carriers induced at the single crystal surfaces of molecular semiconductors. Materials for SC-OFETs are first reviewed with descriptions of the fabrication methods and the field-effect characteristics. In particular, a benchmark carrier mobility of 20-40 cm 2 Vs -1 , achieved with thin platelets of rubrene single crystals, demonstrates the significance of the SC-OFETs and clarifies material limitations for organic devices. In the latter part of this review, we discuss the physics of microscopic charge transport by using SC-OFETs at metal/semiconductor contacts and along semiconductor/insulator interfaces. Most importantly, Hall effect and electron spin resonance (ESR) measurements reveal that interface charge transport in molecular semiconductors is properly described in terms of band transport and localization by charge traps.

Organic field-effect transistors using single crystals

PubMed Central

Hasegawa, Tatsuo; Takeya, Jun

2009-01-01

Organic field-effect transistors using small-molecule organic single crystals are developed to investigate fundamental aspects of organic thin-film transistors that have been widely studied for possible future markets for ‘plastic electronics’. In reviewing the physics and chemistry of single-crystal organic field-effect transistors (SC-OFETs), the nature of intrinsic charge dynamics is elucidated for the carriers induced at the single crystal surfaces of molecular semiconductors. Materials for SC-OFETs are first reviewed with descriptions of the fabrication methods and the field-effect characteristics. In particular, a benchmark carrier mobility of 20–40 cm2 Vs−1, achieved with thin platelets of rubrene single crystals, demonstrates the significance of the SC-OFETs and clarifies material limitations for organic devices. In the latter part of this review, we discuss the physics of microscopic charge transport by using SC-OFETs at metal/semiconductor contacts and along semiconductor/insulator interfaces. Most importantly, Hall effect and electron spin resonance (ESR) measurements reveal that interface charge transport in molecular semiconductors is properly described in terms of band transport and localization by charge traps. PMID:27877287

Synthesis and description of intermolecular interactions in new sulfonamide derivatives of tranexamic acid

NASA Astrophysics Data System (ADS)

Ashfaq, Muhammad; Arshad, Muhammad Nadeem; Danish, Muhammad; Asiri, Abdullah M.; Khatoon, Sadia; Mustafa, Ghulam; Zolotarev, Pavel N.; Butt, Rabia Ayub; Şahin, Onur

2016-01-01

Tranexamic acid (4-aminomethyl-cyclohexanecarboxylic acid) was reacted with sulfonyl chlorides to produce structurally related four sulfonamide derivatives using simple and environmental friendly method to check out their three-dimensional behavior and van der Walls interactions. The molecules were crystallized in different possibilities, as it is/after alkylation at its O and N atoms/along with a co-molecule. All molecules were crystallized in monoclinic crystal system with space group P21/n, P21/c and P21/a. X-ray studies reveal that the molecules stabilized themselves by different kinds of hydrogen bonding interactions. The molecules are getting connected through O-H⋯O hydrogen bonds to form inversion dimers which are further connected through N-H⋯O interactions. The molecules in which N and O atoms were alkylated showed non-classical interaction and generated centro-symmetric R22(24) ring motif. The co-crystallized host and guest molecules are connected to each other via O-H⋯O interactions to generate different ring motifs. By means of the ToposPro software an analysis of the topologies of underlying nets that correspond to molecular packings and hydrogen-bonded networks in structures under consideration was carried out.

A molecular dynamics study of model SI clathrate hydrates: the effect of guest size and guest-water interaction on decomposition kinetics.

PubMed

Das, Subhadip; Baghel, Vikesh Singh; Roy, Sudip; Kumar, Rajnish

2015-04-14

One of the options suggested for methane recovery from natural gas hydrates is molecular replacement of methane by suitable guests like CO2 and N2. This approach has been found to be feasible through many experimental and molecular dynamics simulation studies. However, the long term stability of the resultant hydrate needs to be evaluated; the decomposition rate of these hydrates is expected to depend on the interaction between these guest and water molecules. In this work, molecular dynamics simulation has been performed to illustrate the effect of guest molecules with different sizes and interaction strengths with water on structure I (SI) hydrate decomposition and hence the stability. The van der Waals interaction between water of hydrate cages and guest molecules is defined by Lennard Jones potential parameters. A wide range of parameter spaces has been scanned by changing the guest molecules in the SI hydrate, which acts as a model gas for occupying the small and large cages of the SI hydrate. All atomistic simulation results show that the stability of the hydrate is sensitive to the size and interaction of the guest molecules with hydrate water. The increase in the interaction of guest molecules with water stabilizes the hydrate, which in turn shows a slower rate of hydrate decomposition. Similarly guest molecules with a reasonably small (similar to Helium) or large size increase the decomposition rate. The results were also analyzed by calculating the structural order parameter to understand the dynamics of crystal structure and correlated with the release rate of guest molecules from the solid hydrate phase. The results have been explained based on the calculation of potential energies felt by guest molecules in amorphous water, hydrate bulk and hydrate-water interface regions.

Electrorheological crystallization of proteins and other molecules

DOEpatents

Craig, G.D.; Rupp, B.

1996-06-11

An electrorheological crystalline mass of a molecule is formed by dispersing the molecule in a dispersion fluid and subjecting the molecule dispersion to a uniform electrical field for a period of time during which time an electrorheological crystalline mass is formed. Molecules that may be used to form an electrorheological crystalline mass include any organic or inorganic molecule which has a permanent dipole and/or which is capable of becoming an induced dipole in the presence of an electric field. The molecules used to form the electrorheological crystalline mass are preferably macromolecules, such as biomolecules, such as proteins, nucleic acids, carbohydrates, lipoproteins and viruses. Molecules are crystallized by a method in which an electric field is maintained for a period of time after the electrorheological crystalline mass has formed during which time at least some of the molecules making up the electrorheological crystalline mass form a crystal lattice. The three dimensional structure of a molecule is determined by a method in which an electrorheological crystalline mass of the molecule is formed, an X-ray diffraction pattern of the electrorheological crystalline mass is obtained and the three dimensional structure of the molecule is calculated from the X-ray diffraction pattern. 4 figs.

Electrorheological crystallization of proteins and other molecules

DOEpatents

Craig, George D.; Rupp, Bernhard

1996-01-01

An electrorheological crystalline mass of a molecule is formed by dispersing the molecule in a dispersion fluid and subjecting the molecule dispersion to a uniform electrical field for a period of time during which time an electrorheological crystalline mass is formed. Molecules that may be used to form an electrorheological crystalline mass include any organic or inorganic molecule which has a permanent dipole and/or which is capable of becoming an induced dipole in the presence of an electric field. The molecules used to form the electrorheological crystalline mass are preferably macromolecules, such as biomolecules, such as proteins, nucleic acids, carbohydrates, lipoproteins and viruses. Molecules are crystallized by a method in which an electric field is maintained for a period of time after the electrorheological crystalline mass has formed during which time at least some of the molecules making up the electrorheological crystalline mass form a crystal lattice. The three dimensional structure of a molecule is determined by a method in which an electrorheological crystalline mass of the molecule is formed, an x-ray diffraction pattern of the electrorheological crystalline mass is obtained and the three dimensional structure of the molecule is calculated from the x-ray diffraction pattern.

Nanowires and Nanostructures That Grow Like Polymer Molecules

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shaw, Santosh; Cademartiri, Ludovico

Unique properties (e.g., rubber elasticity, viscoelasticity, folding, reptation) determine the utility of polymer molecules and derive from their morphology (i.e., one-dimensional connectivity and large aspect ratios) and flexibility. Crystals do not display similar properties because they have smaller aspect ratios, they are rigid, and they are often too large and heavy to be colloidally stable. We argue, with the support of recent experimental studies, that these limitations are not fundamental and that they might be overcome by growth processes that mimic polymerization. Furthermore, we (i) discuss the similarities between crystallization and polymerization, (ii) critically review the existing experimental evidence ofmore » polymer-like growth kinetic and behavior in crystals and nanostructures, and (iii) propose heuristic guidelines for the synthesis of “polymer-like” crystals and assemblies. Understanding these anisotropic materials at the boundary between molecules and solids will determine whether we can confer the unique properties of polymer molecules to crystals, expanding them with topology, dynamics, and information and not just tuning them with size.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kuz'mina, L. G., E-mail: kuzmina@igic.ras.ru; Kucherepa, N. S.; Rodnikova, M. N.

The molecular and crystal structures of two p-alkoxybenzylidene)-p'-toluidines C{sub 2}H{sub 5}O-C{sub 6}H{sub 4}-CH=N-C{sub 6}H{sub 4}-CH{sub 3} (1) and C{sub 4}H{sub 9}O-C{sub 6}H{sub 4}-CH=N-C{sub 6}H{sub 4}-CH{sub 3} (2) are determined by X-ray diffraction. Crystals 1 and 2 contain four and two crystallographically independent molecules, respectively. In 1, the geometry of the independent molecules is almost identical. In 2, the independent molecules differ in the conformation of the alkyl chain, which is disordered in one of them. An analysis of the crystal packing of 2 reveals the alternation of spacious layers formed by loosely packed aliphatic fragments of molecules and layers ofmore » closely packed aromatic fragments, which ensures the formation of the mesogenic phase in the course of melting of crystals 2. In crystal 1, loose aliphatic layers are absent.« less

Non-Fullerene Electron Acceptors for Use in Organic Solar Cells

PubMed Central

2015-01-01

Conspectus The active layer in a solution processed organic photovoltaic device comprises a light absorbing electron donor semiconductor, typically a polymer, and an electron accepting fullerene acceptor. Although there has been huge effort targeted to optimize the absorbing, energetic, and transport properties of the donor material, fullerenes remain as the exclusive electron acceptor in all high performance devices. Very recently, some new non-fullerene acceptors have been demonstrated to outperform fullerenes in comparative devices. This Account describes this progress, discussing molecular design considerations and the structure–property relationships that are emerging. The motivation to replace fullerene acceptors stems from their synthetic inflexibility, leading to constraints in manipulating frontier energy levels, as well as poor absorption in the solar spectrum range, and an inherent tendency to undergo postfabrication crystallization, resulting in device instability. New acceptors have to address these limitations, providing tunable absorption with high extinction coefficients, thus contributing to device photocurrent. The ability to vary and optimize the lowest unoccupied molecular orbital (LUMO) energy level for a specific donor polymer is also an important requirement, ensuring minimal energy loss on electron transfer and as high an internal voltage as possible. Initially perylene diimide acceptors were evaluated as promising acceptor materials. These electron deficient aromatic molecules can exhibit good electron transport, facilitated by close packed herringbone crystal motifs, and their energy levels can be synthetically tuned. The principal drawback of this class of materials, their tendency to crystallize on too large a length scale for an optimal heterojunction nanostructure, has been shown to be overcome through introduction of conformation twisting through steric effects. This has been primarily achieved by coupling two units together, forming dimers with a large intramolecular twist, which suppresses both nucleation and crystal growth. The generic design concept of rotationally symmetrical aromatic small molecules with extended π orbital delocalization, including polyaromatic hydrocarbons, phthalocyanines, etc., has also provided some excellent small molecule acceptors. In most cases, additional electron withdrawing functionality, such as imide or ester groups, can be incorporated to stabilize the LUMO and improve properties. New calamitic acceptors have been developed, where molecular orbital hybridization of electron rich and poor segments can be judiciously employed to precisely control energy levels. Conformation and intermolecular associations can be controlled by peripheral functionalization leading to optimization of crystallization length scales. In particular, the use of rhodanine end groups, coupled electronically through short bridged aromatic chains, has been a successful strategy, with promising device efficiencies attributed to high lying LUMO energy levels and subsequently large open circuit voltages. PMID:26505279

Crystal-contact engineering to obtain a crystal form of the Kelch domain of human Keap1 suitable for ligand-soaking experiments.

PubMed

Hörer, Stefan; Reinert, Dirk; Ostmann, Katja; Hoevels, Yvette; Nar, Herbert

2013-06-01

Keap1 is a substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex and plays an important role in the cellular response to oxidative stress. It binds Nrf2 with its Kelch domain and thus triggers the ubiquitinylation and degradation of Nrf2. Oxidative stress prevents the degradation of Nrf2 and leads to the activation of cytoprotective genes. Therefore, Keap1 is an attractive drug target in inflammatory diseases. The support of a medicinal chemistry effort by structural research requires a robust crystallization system in which the crystals are preferably suited for performing soaking experiments. This facilitates the generation of protein-ligand complexes in a routine and high-throughput manner. The structure of human Keap1 has been described previously. In this crystal form, however, the binding site for Nrf2 was blocked by a crystal contact. This interaction was analysed and mutations were introduced to disrupt this crystal contact. One double mutation (E540A/E542A) crystallized in a new crystal form in which the binding site for Nrf2 was not blocked and was accessible to small-molecule ligands. The crystal structures of the apo form of the mutated Keap1 Kelch domain (1.98 Å resolution) and of the complex with an Nrf2-derived peptide obtained by soaking (2.20 Å resolution) are reported.

Chiral Asymmetric Structures in Aspartic Acid and Valine Crystals Assessed by Atomic Force Microscopy.

PubMed

Teschke, Omar; Soares, David Mendez

2016-03-29

Structures of crystallized deposits formed by the molecular self-assembly of aspartic acid and valine on silicon substrates were imaged by atomic force microscopy. Images of d- and l-aspartic acid crystal surfaces showing extended molecularly flat sheets or regions separated by single molecule thick steps are presented. Distinct orientation surfaces were imaged, which, combined with the single molecule step size, defines the geometry of the crystal. However, single molecule step growth also reveals the crystal chirality, i.e., growth orientations. The imaged ordered lattice of aspartic acid (asp) and valine (val) mostly revealed periodicities corresponding to bulk terminations, but a previously unreported molecular hexagonal lattice configuration was observed for both l-asp and l-val but not for d-asp or d-val. Atomic force microscopy can then be used to identify the different chiral forms of aspartic acid and valine crystals.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kuz'mina, L. G., E-mail: kuzmina@igic.ras.ru; Sitin, A. G.; Gulakova, E. N.

The crystal and molecular structures of five styrylheterocycles of the quinoline series are studied. All molecules are planar. The double bond in the ethylene fragment is essentially localized. In the molecule of 2-(4-methylstyryl)quinoline, the ethylene fragment is disordered by the bicycle-pedal pattern. In four of the five compounds, the crystal packings do not contain stacking dimers prearranged for the [2+2] photocycloaddition (PCA) reaction. In the crystal of 2-(3-nitrostyryl)quinoline, pairs of crystallographically independent molecules form stacking dimers. In a dimer, the ethylene fragments have a twist orientation, which is incompatible with the PCA reaction. An attempt to initiate a temperature-dependent processmore » of bicyclepedal isomerization in the crystal and, as a consequence, the PCA reaction by means of simultaneous irradiation and heating of a single crystal is unsuccessful.« less

The effect of pressure on open-framework silicates: elastic behaviour and crystal-fluid interaction

NASA Astrophysics Data System (ADS)

Gatta, G. D.; Lotti, P.; Tabacchi, G.

2018-02-01

The elastic behaviour and the structural evolution of microporous materials compressed hydrostatically in a pressure-transmitting fluid are drastically affected by the potential crystal-fluid interaction, with a penetration of new molecules through the zeolitic cavities in response to applied pressure. In this manuscript, the principal mechanisms that govern the P-behaviour of zeolites with and without crystal-fluid interaction are described, on the basis of previous experimental findings and computational modelling studies. When no crystal-fluid interaction occurs, the effects of pressure are mainly accommodated by tilting of (quasi-rigid) tetrahedra around O atoms that behave as hinges. Tilting of tetrahedra is the dominant mechanism at low-mid P-regime, whereas distortion and compression of tetrahedra represent the mechanisms which usually dominate the mid-high P regime. One of the most common deformation mechanisms in zeolitic framework is the increase of channels ellipticity. The deformation mechanisms are dictated by the topological configuration of the tetrahedral framework; however, the compressibility of the cavities is controlled by the nature and bonding configuration of the ionic and molecular content, resulting in different unit-cell volume compressibility in isotypic structures. The experimental results pertaining to compression in "penetrating" fluids, and thus with crystal-fluid interaction, showed that not all the zeolites experience a P-induced intrusion of new monoatomic species or molecules from the P-transmitting fluids. For example, zeolites with well-stuffed channels at room conditions (e.g. natural zeolites) tend to hinder the penetration of new species through the zeolitic cavities. Several variables govern the sorption phenomena at high pressure, among those: the "free diameters" of the framework cavities, the chemical nature and the configuration of the extra-framework population, the partial pressure of the penetrating molecule in the fluid (if mixed with other non-penetrating molecules), the rate of P-increase, the surface/volume ratio of the crystallites under investigations and the temperature at which the experiment is conducted. An overview of the intrusion phenomena of monoatomic species (e.g. He, Ar, Kr), small (e.g. H2O, CO2) and complex molecules, along with the P-induced polymerization phenomena (e.g. C2H2, C2H4, C2H6O, C2H6O2, BNH6, electrolytic MgCl2·21H2O solution) is provided, with a discussion of potential technological and geological implications of these experimental findings.

Interactions of molecules and the properties of crystals

NASA Astrophysics Data System (ADS)

McConnell, Thomas Daniel Leigh

In this thesis the basic theory of the lattice dynamics of molecular crystals is considered, with particular reference to the specific case of linear molecules. The objective is to carry out a critical investigation of a number of empirical potentials as models for real systems. Suitable coordinates are introduced, in particular vibrational coordinates which are used to describe the translational and rotational modes of the free molecule. The Taylor expansion of the intermolecular potential is introduced and its terms considered, in particular the (first-order) equilibrium conditions for such a system and the (second-order) lattice vibrations. The elastic properties are also considered, in particular with reference to the specific case of rhombohedral crystals. The compressibility and a number of conditions for elastic stability are introduced. The total intermolecular interaction potential is divided into three components using perturbation methods, the electrostatic energy, the repulsion energy and the dispersion energy. A number of models are introduced for these various components. The induction energy is neglected. The electrostatic interaction is represented by atomic multipole and molecular multipole models. The repulsion and dispersion energies are modelled together in a central interaction potential, either the Lennard-Jones atom-atom potential or the anisotropic Berne-Pechukas molecule-molecule potential. In each case, the Taylor expansion coefficients, used to calculate the various molecular properties, are determined. An algorithm is described which provides a relatively simple method for calculating cartesian tensors, which are found in the Taylor expansion coefficients of the multipolar potentials. This proves to be particularly useful from a computational viewpoint, both in terms of programming and calculating efficiency. The model system carbonyl sulphide is introduced and its lattice properties are described. Suitable parameters for potentials used to model the system are discussed and the simplifications to the Taylor expansion coefficients due to crystal symmetry are detailed. Four potential parameters are chosen to be fitted to four lattice properties, representing zero, first and second order Taylor expansion coefficients. The supplementary tests of a given fitted potential are detailed. A number of forms for the electrostatic interaction of carbonyl sulphide are considered, each combined with a standard atom-atom potential. The success of the molecular octupole model is considered and the inability of more complex electrostatic potentials to improve on this simple model is noted. The anisotropic Berne-Pechukas potential, which provides an increased estimate of the compressibility is considered as being an improvement on the various atom-atom potentials. The effect of varying the exponents in the atom-atom (or molecule-molecule) potential, representing a systematic variation of the repulsion and dispersion energy models, is examined and a potential which is able to reproduce all of the given lattice properties for carbonyl sulphide is obtained. The molecular crystal of cyanogen iodide is investigated. Superficially it is similar to the crystal of carbonyl sulphide and the potentials used with success for the latter are applied to cyanogen iodide to determine whether they are equally as effective models for this molecule. These potentials are found to be far less successful, in all cases yielding a number of unrealistic results. Reasons for the failure of the model are considered, in particular the 3 differences between the electrostatic properties of the two molecules are discussed. It is concluded that some of the simplifications which proved satisfactory for carbonyl sulphide are invalid for simple extension to the case of cyanogen iodide. A first estimate of the differences in the electrostatic properties is attempted, calculating the induction energies of the two molecules. The assumption that the induction energy may be neglected is justified for the case of carbonyl sulphide but found to be far less satisfactory for cyanogen iodide. Finally details of ab initio calculations are outlined. The amount of experimental data available for the electrostatic properties of the two molecules under consideration is relatively small and the experimental data which is available is supplemented by values obtained from these calculations.

Microgravity

NASA Image and Video Library

2001-06-06

Gravity or density-driven convection occurs as protein molecules incorporate into a crystal lattice from the surrounding solution. The layer bordering the crystal (the depletion zone) then contains a less-dense protein concentration, causing the layer to rise. The remaining, denser solution sinks because of gravity, creating eddies that make it difficult for more protein molecules to attach to the crystal in an ordered way.

Mapping a disordered portion of the Brz2001-binding site on a plant monooxygenase, DWARF4, using a quartz-crystal microbalance biosensor-based T7 phage display.

PubMed

Takakusagi, Yoichi; Manita, Daisuke; Kusayanagi, Tomoe; Izaguirre-Carbonell, Jesus; Takakusagi, Kaori; Kuramochi, Kouji; Iwabata, Kazuki; Kanai, Yoshihiro; Sakaguchi, Kengo; Sugawara, Fumio

2013-04-01

In small-molecule/protein interaction studies, technical difficulties such as low solubility of small molecules or low abundance of protein samples often restrict the progress of research. Here, we describe a quartz-crystal microbalance (QCM) biosensor-based T7 phage display in combination use with a receptor-ligand contacts (RELIC) bioinformatics server for application in a plant Brz2001/DWARF4 system. Brz2001 is a brassinosteroid biosynthesis inhibitor in the less-soluble triazole series of compounds that targets DWARF4, a cytochrome P450 (Cyp450) monooxygenase containing heme and iron. Using a Brz2001 derivative that has higher solubility in 70% EtOH and forms a self-assembled monolayer on gold electrode, we selected 34 Brz2001-recognizing peptides from a 15-mer T7 phage-displayed random peptide library using a total of four sets of one-cycle biopanning. The RELIC/MOTIF program revealed continuous and discontinuous short motifs conserved within the 34 Brz2001-selected 15-mer peptide sequences, indicating the increase of information content for Brz2001 recognition. Furthermore, an analysis of similarity between the 34 peptides and the amino-acid sequence of DWARF4 using the RELIC/MATCH program generated a similarity plot and a cluster diagram of the amino-acid sequence. Both of these data highlighted an internally located disordered portion of a catalytic site on DWARF4, indicating that this portion is essential for Brz2001 recognition. A similar trend was also noted by an analysis using another 26 Brz2001-selected peptides, and not observed using the 27 gold electrode-recognizing control peptides, demonstrating the reproducibility and specificity of this method. Thus, this affinity-based strategy enables high-throughput detection of the small-molecule-recognizing portion on the target protein, which overcomes technical difficulties such as sample solubility or preparation that occur when conventional methods are used.

Apparatus for mixing solutions in low gravity environments

NASA Technical Reports Server (NTRS)

Carter, Daniel C. (Inventor); Broom, Mary B. (Inventor)

1990-01-01

An apparatus is disclosed for allowing mixing of solutions in low gravity environments so as to carry out crystallization of proteins and other small molecules or other chemical syntheses, under conditions that maximize crystal growth and minimize disruptive turbulent effects. The apparatus is comprised of a housing, a plurality of chambers, and a cylindrical rotatable valve disposed between at least two of the chambers, said valve having an internal passageway so as to allow fluid movement between the chambers by rotation of the valve. In an alternate embodiment of the invention, a valve is provided having an additional internal passage way so that fluid from a third chamber can be mixed with the fluids of the first two chambers. This alternate embodiment of the invention is particularly desirable when it is necessary to provide a termination step to the crystal growth, or if a second synthetic step is required.

Validation of missed space-group symmetry in X-ray powder diffraction structures with dispersion-corrected density functional theory.

PubMed

Hempler, Daniela; Schmidt, Martin U; van de Streek, Jacco

2017-08-01

More than 600 molecular crystal structures with correct, incorrect and uncertain space-group symmetry were energy-minimized with dispersion-corrected density functional theory (DFT-D, PBE-D3). For the purpose of determining the correct space-group symmetry the required tolerance on the atomic coordinates of all non-H atoms is established to be 0.2 Å. For 98.5% of 200 molecular crystal structures published with missed symmetry, the correct space group is identified; there are no false positives. Very small, very symmetrical molecules can end up in artificially high space groups upon energy minimization, although this is easily detected through visual inspection. If the space group of a crystal structure determined from powder diffraction data is ambiguous, energy minimization with DFT-D provides a fast and reliable method to select the correct space group.

Slow light enhanced gas sensing in photonic crystals

NASA Astrophysics Data System (ADS)

Kraeh, Christian; Martinez-Hurtado, J. L.; Popescu, Alexandru; Hedler, Harry; Finley, Jonathan J.

2018-02-01

Infrared spectroscopy allows for highly selective and highly sensitive detection of gas species and concentrations. Conventional gas spectrometers are generally large and unsuitable for on-chip applications. Long absorption path lengths are usually required and impose a challenge for miniaturization. In this work, a gas spectrometer is developed consisting of a microtube photonic crystal structure. This structure of millimetric form factors minimizes the required absorption path length due to slow light effects. The microtube photonic crystal allows for strong transmission in the mid-infrared and, due to its large void space fraction, a strong interaction between light and gas molecules. As a result, enhanced absorption of light increases the gas sensitivity of the device. Slow light enhanced gas absorption by a factor of 5.8 in is experimentally demonstrated at 5400 nm. We anticipate small form factor gas sensors on silicon to be a starting point for on-chip gas sensing architectures.

Coarse gaining of molecular crystals: limitations imposed by molecular flexibility

NASA Astrophysics Data System (ADS)

Picu, Catalin; Pal, Anirban

Molecular crystals include molecular electronics, energetic materials, pharmaceuticals and some food components. In many of these applications the small scale mechanical behavior of the crystal is important such as for example in energetic materials where detonation is induced by the formation of hot spots which are induced thermomechanically, and in pharmaceuticals where phase stability is critical for the biochemical activity of the drug. Accurate modeling of these processes requires resolving the atomistic scale details of the material. However, the cost of these models is very large due to the complexity of the molecules forming the crystal, and some form of coarse graning is necessary. In this study we identify the limitations imposed by the need to accurately capture molecular flexibility on the development of coarse grained models for the energetic molecular crystal RDX. We define guidelines for the definition of coarse grained models that target elastic and plastic crystal scale properties such as elastic constants, thermal expansion, compressibility, the critical stress for the motion of dislocations (Peierls stress) and the stacking fault energy This work was supported by the ARO through Grant W911NF-09-1-0330 and AFRL through Grant FA8651-16-1-0004.

Introduction to protein crystallization

PubMed Central

McPherson, Alexander; Gavira, Jose A.

2014-01-01

Protein crystallization was discovered by chance about 150 years ago and was developed in the late 19th century as a powerful purification tool and as a demonstration of chemical purity. The crystallization of proteins, nucleic acids and large biological complexes, such as viruses, depends on the creation of a solution that is supersaturated in the macromolecule but exhibits conditions that do not significantly perturb its natural state. Supersaturation is produced through the addition of mild precipitating agents such as neutral salts or polymers, and by the manipulation of various parameters that include temperature, ionic strength and pH. Also important in the crystallization process are factors that can affect the structural state of the macromolecule, such as metal ions, inhibitors, cofactors or other conventional small molecules. A variety of approaches have been developed that combine the spectrum of factors that effect and promote crystallization, and among the most widely used are vapor diffusion, dialysis, batch and liquid–liquid diffusion. Successes in macromolecular crystallization have multiplied rapidly in recent years owing to the advent of practical, easy-to-use screening kits and the application of laboratory robotics. A brief review will be given here of the most popular methods, some guiding principles and an overview of current technologies. PMID:24419610

Introduction to protein crystallization.

PubMed

McPherson, Alexander; Gavira, Jose A

2014-01-01

Protein crystallization was discovered by chance about 150 years ago and was developed in the late 19th century as a powerful purification tool and as a demonstration of chemical purity. The crystallization of proteins, nucleic acids and large biological complexes, such as viruses, depends on the creation of a solution that is supersaturated in the macromolecule but exhibits conditions that do not significantly perturb its natural state. Supersaturation is produced through the addition of mild precipitating agents such as neutral salts or polymers, and by the manipulation of various parameters that include temperature, ionic strength and pH. Also important in the crystallization process are factors that can affect the structural state of the macromolecule, such as metal ions, inhibitors, cofactors or other conventional small molecules. A variety of approaches have been developed that combine the spectrum of factors that effect and promote crystallization, and among the most widely used are vapor diffusion, dialysis, batch and liquid-liquid diffusion. Successes in macromolecular crystallization have multiplied rapidly in recent years owing to the advent of practical, easy-to-use screening kits and the application of laboratory robotics. A brief review will be given here of the most popular methods, some guiding principles and an overview of current technologies.

Microgravity

NASA Image and Video Library

2001-06-06

Atomic force microscopy uses laser technology to reveal a defect, a double-screw dislocation, on the surface of this crystal of canavalin, a major source of dietary protein for humans and domestic animals. When a crystal grows, attachment kinetics and transport kinetics are competing for control of the molecules. As a molecule gets close to the crystal surface, it has to attach properly for the crystal to be usable. NASA has funded investigators to look at those attachment kinetics from a theoretical standpoint and an experimental standpoint. Dr. Alex McPherson of the University of California, Irvine, is one of those investigators. He uses X-ray diffraction and atomic force microscopy in his laboratory to answer some of the many questions about how protein crystals grow. Atomic force microscopy provides a means of looking at how individual molecules are added to the surface of growing protein crystals. This helps McPherson understand the kinetics of protein crystal growth. McPherson asks, How fast do crystals grow? What are the forces involved? Investigators funded by NASA have clearly shown that such factors as the level of supersaturation and the rate of growth all affect the habit [characteristic arrangement of facets] of the crystal and the defects that occur in the crystal.

Structural and computational study of 1,2,4-triazolin-5-thione derivative and its DMSO solvate

NASA Astrophysics Data System (ADS)

Dybała, Izabela; Wawrzycka-Gorczyca, Irena; Struga, Marta

2017-11-01

The solid state structure of 3-(4-phenyl-5-oxo-1,2,4-triazolin-1-ylmethyl)-4-cyclohexyl-1,2,4-triazolin-5-thione (1) was characterized by FT-IR and X-ray diffraction experiment. Additionally, molecular and crystal structure of its DMSO solvate (1DMSO) has been determined by X-ray diffraction method. The influence of DMSO molecules incorporation to the crystal lattice on geometry of triazolin-5-thione derivative molecule and crystal packing was analyzed. Non-covalent bonds within the crystals are additionally visualized by determination of Hirshfeld surfaces. According to results of conformational analysis in gas, molecule of triazolin-5-thione derivative adopts the lowest energy conformation in 1DMSO crystal. The crystal structure of 1 and 1DMSO were compared with previously described structurally similar compounds, in which the cyclohexyl substituent was replaced by aromatic one (phenyl/methoxyphenyl). Very interesting differences in molecules association were found by comparing the crystal structures of 1 and 1DMSO with their, mentioned above, aromatic derivatives. Interesting properties of triazolin-5-thione derivatives are connected with their π-electron delocalization effects, thus aromaticity of heterocyclic fragments has been investigated by means of the HOMA index. Comparison of aromaticity calculations results with association tendency of molecules shows that triazolin-5-one fragments reach higher aromaticity when nitrogen atom from this moiety acts as a donor in strong Nsbnd H⋯N hydrogen bonds.

Protein crystals and their growth

NASA Technical Reports Server (NTRS)

Chernov, Alexander A.

2003-01-01

Recent results on the associations between protein molecules in crystal lattices, crystal-solution surface energy, elastic properties, strength, and spontaneous crystal cracking are reviewed and discussed. In addition, some basic approaches to understanding the solubility of proteins are followed by an overview of crystal nucleation and growth. It is argued that variability of mixing in batch crystallization may be a source of the variation in the number of crystals ultimately appearing in the sample. The frequency at which new molecules join a crystal lattice is measured by the kinetic coefficient and is related to the observed crystal growth rate. Numerical criteria used to discriminate diffusion- and kinetic-limited growth are discussed on this basis. Finally, the creation of defects is discussed with an emphasis on the role of impurities and convection on macromolecular crystal perfection.

Quasi-Phase Diagrams at Air/Oil Interfaces and Bulk Oil Phases for Crystallization of Small-Molecular Semiconductors by Adjusting Gibbs Adsorption.

PubMed

Watanabe, Satoshi; Ohta, Takahisa; Urata, Ryota; Sato, Tetsuya; Takaishi, Kazuto; Uchiyama, Masanobu; Aoyama, Tetsuya; Kunitake, Masashi

2017-09-12

The temperature and concentration dependencies of the crystallization of two small-molecular semiconductors were clarified by constructing quasi-phase diagrams at air/oil interfaces and in bulk oil phases. A quinoidal quaterthiophene derivative with four alkyl chains (QQT(CN)4) in 1,1,2,2-tetrachroloethane (TCE) and a thienoacene derivative with two alkyl chains (C8-BTBT) in o-dichlorobenzene were used. The apparent crystal nucleation temperature (T n ) and dissolution temperature (T d ) of the molecules were determined based on optical microscopy examination in closed glass capillaries and open dishes during slow cooling and heating processes, respectively. T n and T d were considered estimates of the critical temperatures for nuclear formation and crystal growth, respectively. The T n values of QQT(CN)4 and C8-BTBT at the air/oil interfaces were higher than those in the bulk oil phases, whereas the T d values at the air/oil interfaces were almost the same as those in the bulk oil phases. These Gibbs adsorption phenomena were attributed to the solvophobic effect of the alkyl chain moieties. The temperature range between T n and T d corresponds to suitable supercooling conditions for ideal crystal growth based on the suppression of nucleation. The T n values at the water/oil and oil/glass interfaces did not shift compared with those of the bulk phases, indicating that adsorption did not occur at the hydrophilic interfaces. Promotion and inhibition of nuclear formation for crystal growth of the semiconductors were achieved at the air/oil and hydrophilic interfaces, respectively.

3D DNA Crystals and Nanotechnology

DOE Office of Scientific and Technical Information (OSTI.GOV)

Paukstelis, Paul; Seeman, Nadrian

DNA's molecular recognition properties have made it one of the most widely used biomacromolecular construction materials. The programmed assembly of DNA oligonucleotides has been used to create complex 2D and 3D self-assembled architectures and to guide the assembly of other molecules. The origins of DNA nanotechnology are rooted in the goal of assembling DNA molecules into designed periodic arrays, i.e., crystals. Here, we highlight several DNA crystal structures, the progress made in designing DNA crystals, and look at the current prospects and future directions of DNA crystals in nanotechnology.

3D DNA Crystals and Nanotechnology

DOE PAGES

Paukstelis, Paul; Seeman, Nadrian

2016-08-18

DNA's molecular recognition properties have made it one of the most widely used biomacromolecular construction materials. The programmed assembly of DNA oligonucleotides has been used to create complex 2D and 3D self-assembled architectures and to guide the assembly of other molecules. The origins of DNA nanotechnology are rooted in the goal of assembling DNA molecules into designed periodic arrays, i.e., crystals. Here, we highlight several DNA crystal structures, the progress made in designing DNA crystals, and look at the current prospects and future directions of DNA crystals in nanotechnology.

Crystallization and textural porosity of synthetic clay minerals.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Carrado, K. A.; Csencsits, R.; Thiyagarajan, P.

2002-12-01

The crystallization of synthetic layered magnesium silicate hectorite clays from both silica sol and organosilane sources is compared. For the silica sol-derived clays, a templating method is employed wherein organic or polymeric molecules are included during clay crystallization that are then removed from the composites via calcination. The mechanism of silane-derived hectorite formation is followed by XRD, TGA, 29Si MAS NMR, and small angle X-ray scattering (SAXS), and results are compared to those obtained for the sol-derived hectorite. The mechanism appears to be similar but the rate is approximately doubled when the silane is used rather than silica sol. Analyticalmore » transmission electron microscopy (TEM) is exploited to glean structural morphology information towards resolving the nature of the resulting pore network structures. Results are compared with nitrogen adsorption-desorption isotherm behavior; dominant hysteresis loops are present in the type IV isotherms. Pore size distributions based on both the adsorption and desorption isotherms are compared. Small angle neutron scattering (SANS) experiments reveal that the average particle size increases as synthetic laponite < sol-derived hectorite < silane-derived hectorite < natural hectorite. Contrast matching SANS studies in aqueous and organic solvents are carried out to extract information about pore accessibility.« less

Expression and Purification of EPHA2 Tyrosine Kinase Domain for Crystallographic and NMR Studies.

PubMed

Gande, Santosh L; Saxena, Krishna; Sreeramulu, Sridhar; Linhard, Verena; Kudlinzki, Denis; Heinzlmeir, Stephanie; Reichert, Andreas J; Skerra, Arne; Kuster, Bernhard; Schwalbe, Harald

2016-12-02

The receptor tyrosine kinase EPHA2 is overexpressed in several cancers (breast, head and neck, non-small-cell lung cancer). Small-molecule-based inhibition of the EPHA2 kinase domain (KD) is seen as an important strategy for therapeutic intervention. However, obtaining structural information by crystallography or NMR spectroscopy for drug discovery is severely hampered by the lack of pure, homogeneous protein. Here, different fragments of the EPHA2 KD were expressed and purified from both bacterial (Escherichia coli, BL21(DE3) cells) and insect cells (Spodoptera frugiperda, Sf9 cells). 1 H, 15 N HSQC was used to determine the proper folding and homogeneity of all the constructs. Protein from E. coli was well-folded but unstable, and it did not crystallize. However, a construct (D596-G900) produced in Sf9 cells yielded homogenous, well-folded protein that crystallized readily, thereby resulting in eleven new EPHA2-ligand crystal structures. We have also established a strategy for selective and uniform 15 N-amino acid labeling of EPHA2 KD in Sf9 cells for investigating dynamics and EPHA2-drug interactions by NMR. © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Discovery and structure-based design of 4,6-diaminonicotinamides as potent and selective IRAK4 inhibitors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bhide, Rajeev S.; Keon, Alec; Weigelt, Carolyn

2017-11-01

The identification of small molecule inhibitors of IRAK4 for the treatment of autoimmune diseases has been an area of intense research. We discovered novel 4,6-diaminonicotinamides which potently inhibit IRAK4. Optimization efforts were aided by X-ray crystal structures of inhibitors bound to IRAK4. Structure activity relationship (SAR) studies led to the identification of compound 29 which exhibited sub-micromolar potency in a LTA stimulated cellular assay.

Phase transitions of antibiotic clarithromycin forms I, IV and new form VII crystals.

PubMed

Ito, Masataka; Shiba, Rika; Watanabe, Miteki; Iwao, Yasunori; Itai, Shigeru; Noguchi, Shuji

2018-06-01

Metastable crystal form I of the antibiotic clarithromycin has a pharmaceutically valuable characteristic that its crystalline phase transition can be applied for its sustained release from tablets. The phase transition of form I was investigated in detail by single crystal and powder X-ray analyses, dynamic vapor sorption analysis and thermal analysis. The single crystal structure of form I revealed that form I was not an anhydrate crystal but contained a partially occupied water molecule in the channel-like void space. Dynamic vapor sorption (DVS) analysis demonstrated that form I crystals reversibly sorbed water molecules in two steps when the relative humidity (RH) increased and finally transited to hydrate form IV at 95% RH. DVS analysis also showed that when the RH decreased form IV crystals lost water molecules at 40% RH and transited to the newly identified anhydrate crystal form VII. Form VII reversibly transited to form IV at lower RH than form I, suggesting that form I is more suitable for manufacturing a sustained-release tablet of CAM utilizing the crystalline phase transition. Copyright © 2018 Elsevier B.V. All rights reserved.

Designing small molecules to target cryptic pockets yields both positive and negative allosteric modulators

PubMed Central

Moeder, Katelyn E.; Ho, Chris M. W.; Zimmerman, Maxwell I.; Frederick, Thomas E.; Bowman, Gregory R.

2017-01-01

Allosteric drugs, which bind to proteins in regions other than their main ligand-binding or active sites, make it possible to target proteins considered “undruggable” and to develop new therapies that circumvent existing resistance. Despite growing interest in allosteric drug discovery, rational design is limited by a lack of sufficient structural information about alternative binding sites in proteins. Previously, we used Markov State Models (MSMs) to identify such “cryptic pockets,” and here we describe a method for identifying compounds that bind in these cryptic pockets and modulate enzyme activity. Experimental tests validate our approach by revealing both an inhibitor and two activators of TEM β-lactamase (TEM). To identify hits, a library of compounds is first virtually screened against either the crystal structure of a known cryptic pocket or an ensemble of structures containing the same cryptic pocket that is extracted from an MSM. Hit compounds are then screened experimentally and characterized kinetically in individual assays. We identify three hits, one inhibitor and two activators, demonstrating that screening for binding to allosteric sites can result in both positive and negative modulation. The hit compounds have modest effects on TEM activity, but all have higher affinities than previously identified inhibitors, which bind the same cryptic pocket but were found, by chance, via a computational screen targeting the active site. Site-directed mutagenesis of key contact residues predicted by the docking models is used to confirm that the compounds bind in the cryptic pocket as intended. Because hit compounds are identified from docking against both the crystal structure and structures from the MSM, this platform should prove suitable for many proteins, particularly targets whose crystal structures lack obvious druggable pockets, and for identifying both inhibitory and activating small-molecule modulators. PMID:28570708

More than a simple lipophilic contact: a detailed thermodynamic analysis of nonbasic residues in the s1 pocket of thrombin.

PubMed

Baum, Bernhard; Mohamed, Menshawy; Zayed, Mohamed; Gerlach, Christof; Heine, Andreas; Hangauer, David; Klebe, Gerhard

2009-07-03

The field of medicinal chemistry aims to design and optimize small molecule leads into drug candidates that may positively interfere with pathological disease situations in humans or combat the growth of infective pathogens. From the plethora of crystal structures of protein-inhibitor complexes we have learned how molecules recognize each other geometrically, but we still have rather superficial understanding of why they bind to each other. This contribution surveys a series of 26 thrombin inhibitors with small systematic structural differences to elucidate the rationale for their widely deviating binding affinity from 185 microM to 4 nM as recorded by enzyme kinetic measurements. Five well-resolved (resolution 2.30 - 1.47 A) crystal structures of thrombin-inhibitor complexes and an apo-structure of the uncomplexed enzyme (1.50 A) are correlated with thermodynamic data recorded by isothermal titration calorimetry with 12 selected inhibitors from the series. Taking solubility data into account, the variation in physicochemical properties allows conclusions to be reached about the relative importance of the enthalpic binding features as well as to estimate the importance of the parameters more difficult to capture, such as residual ligand entropy and desolvation properties. The collected data reveal a comprehensive picture of the thermodynamic signature that explains the so far poorly understood attractive force experienced by m-chloro-benzylamides to thrombin.

Antibodies under pressure: A Small-Angle X-ray Scattering study of Immunoglobulin G under high hydrostatic pressure.

PubMed

König, Nico; Paulus, Michael; Julius, Karin; Schulze, Julian; Voetz, Matthias; Tolan, Metin

2017-12-01

In the present work two subclasses of the human antibody Immunoglobulin G (IgG) have been investigated by Small-Angle X-ray Scattering under high hydrostatic pressures up to 5kbar. It is shown that IgG adopts a symmetric T-shape in solution which differs significantly from available crystal structures. Moreover, high-pressure experiments verify the high stability of the IgG molecule. It is not unfolded by hydrostatic pressures of up to 5kbar but a slight increase of the radius of gyration was observed at elevated pressures. Copyright © 2017 Elsevier B.V. All rights reserved.

Enterobactin: An archetype for microbial iron transport

PubMed Central

Raymond, Kenneth N.; Dertz, Emily A.; Kim, Sanggoo S.

2003-01-01

Bacteria have aggressive acquisition processes for iron, an essential nutrient. Siderophores are small iron chelators that facilitate cellular iron transport. The siderophore enterobactin is a triscatechol derivative of a cyclic triserine lactone. Studies of the chemistry, regulation, synthesis, recognition, and transport of enterobactin make it perhaps the best understood of the siderophore-mediated iron uptake systems, displaying a lot of function packed into this small molecule. However, recent surprises include the isolation of corynebactin, a closely related trithreonine triscatechol derivative lactone first found in Gram-positive bacteria, and the crystal structure of a ferric enterobactin complex of a protein identified as an antibacterial component of the human innate immune system. PMID:12655062

Amino Acid-Assisted Incorporation of Dye Molecules within Calcite Crystals.

PubMed

Marzec, Bartosz; Green, David C; Holden, Mark A; Coté, Alexander S; Ihli, Johannes; Khalid, Saba; Kulak, Alexander; Walker, Daniel; Tang, Chiu; Duffy, Dorothy M; Kim, Yi-Yeoun; Meldrum, Fiona C

2018-05-23

Biomineralisation processes invariably occur in the presence of multiple organic additives, which act in combination to give exceptional control over structures and properties. However, few synthetic studies have investigated the cooperative effects of soluble additives. This work addresses this challenge and focuses on the combined effects of amino acids and coloured dye molecules. The experiments demonstrate that strongly coloured calcite crystals only form in the presence of Brilliant Blue R (BBR) and four of the seventeen soluble amino acids, as compared with almost colourless crystals using the dye alone. The active amino acids are identified as those which themselves effectively occlude in calcite, suggesting a mechanism where they can act as chaperones for individual molecules or even aggregates of dyes molecules. These results provide new insight into crystal-additive interactions and suggest a novel strategy for generating materials with target properties. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

THz-IR spectroscopy of single H2O molecules confined in nanocage of beryl crystal lattice

NASA Astrophysics Data System (ADS)

Gorshunov, Boris P.; Zhukova, Elena S.; Torgashev, Victor I.; Motovilova, Elizaveta A.; Lebedev, Vladimir V.; Prokhorov, Anatoly S.; Shakurov, Gil'man S.; Kremer, Reinhard K.; Uskov, Vladimir V.; Pestrjakov, Efim V.; Thomas, Victor G.; Fursenko, Dimitri A.; Kadlec, Christelle; Kadlec, Filip; Dressel, Martin

2014-11-01

We have measured the terahertz-infrared (3-7000 cm-1) spectra of the optical conductivity of iron-doped single crystals of beryl, (Mn,Fe):Be3Al2Si6O18, that contain lone water molecules isolated within nanometer-sized cages formed by the ions of beryl crystal lattice. By comparing the spectra with those of dehydrated crystals, we exclude phonon resonances and reconstruct the spectra determined exclusively by vibrations of the water molecules. At liquid-helium temperatures, well-known intramolecular H2O modes are observed above 1000 cm-1 and accompanied with satellite resonances that are combinations of intramolecular and external vibrations of H2O molecules. At terahertz frequencies, a broad bump centred around 20 cm-1 (at 5 K) is observed with three rather narrow resonances at its high-frequency shoulder (38, 42 and 46 cm-1). The origin of these low-energy excitations is discussed.

A new model for simulating 3-d crystal growth and its application to the study of antifreeze proteins.

PubMed

Wathen, Brent; Kuiper, Michael; Walker, Virginia; Jia, Zongchao

2003-01-22

A novel computational technique for modeling crystal formation has been developed that combines three-dimensional (3-D) molecular representation and detailed energetics calculations of molecular mechanics techniques with the less-sophisticated probabilistic approach used by statistical techniques to study systems containing millions of molecules undergoing billions of interactions. Because our model incorporates both the structure of and the interaction energies between participating molecules, it enables the 3-D shape and surface properties of these molecules to directly affect crystal formation. This increase in model complexity has been achieved while simultaneously increasing the number of molecules in simulations by several orders of magnitude over previous statistical models. We have applied this technique to study the inhibitory effects of antifreeze proteins (AFPs) on ice-crystal formation. Modeling involving both fish and insect AFPs has produced results consistent with experimental observations, including the replication of ice-etching patterns, ice-growth inhibition, and specific AFP-induced ice morphologies. Our work suggests that the degree of AFP activity results more from AFP ice-binding orientation than from AFP ice-binding strength. This technique could readily be adapted to study other crystal and crystal inhibitor systems, or to study other noncrystal systems that exhibit regularity in the structuring of their component molecules, such as those associated with the new nanotechnologies.

[Fine stereo structure for natural organic molecules, a preliminary study. II. Melting point influenced by structure factors].

PubMed

Lu, Y; Zheng, Q; Lu, D; Ma, P; Chen, Y

1995-06-01

Crystal structures of two compounds from Tripterygium wilfordii Hook f. have been determined by X-ray diffraction method. Structure factors influencing melting point of solid state have been analysed. Crystal class (or space group), recrystallization solvent, force between molecules and fine changes of molecular structures will all cause melting point changes of crystal substance.

Optimization of crystallization conditions for biological macromolecules.

PubMed

McPherson, Alexander; Cudney, Bob

2014-11-01

For the successful X-ray structure determination of macromolecules, it is first necessary to identify, usually by matrix screening, conditions that yield some sort of crystals. Initial crystals are frequently microcrystals or clusters, and often have unfavorable morphologies or yield poor diffraction intensities. It is therefore generally necessary to improve upon these initial conditions in order to obtain better crystals of sufficient quality for X-ray data collection. Even when the initial samples are suitable, often marginally, refinement of conditions is recommended in order to obtain the highest quality crystals that can be grown. The quality of an X-ray structure determination is directly correlated with the size and the perfection of the crystalline samples; thus, refinement of conditions should always be a primary component of crystal growth. The improvement process is referred to as optimization, and it entails sequential, incremental changes in the chemical parameters that influence crystallization, such as pH, ionic strength and precipitant concentration, as well as physical parameters such as temperature, sample volume and overall methodology. It also includes the application of some unique procedures and approaches, and the addition of novel components such as detergents, ligands or other small molecules that may enhance nucleation or crystal development. Here, an attempt is made to provide guidance on how optimization might best be applied to crystal-growth problems, and what parameters and factors might most profitably be explored to accelerate and achieve success.

Optimization of crystallization conditions for biological macromolecules

PubMed Central

McPherson, Alexander; Cudney, Bob

2014-01-01

For the successful X-ray structure determination of macromolecules, it is first necessary to identify, usually by matrix screening, conditions that yield some sort of crystals. Initial crystals are frequently microcrystals or clusters, and often have unfavorable morphologies or yield poor diffraction intensities. It is therefore generally necessary to improve upon these initial conditions in order to obtain better crystals of sufficient quality for X-ray data collection. Even when the initial samples are suitable, often marginally, refinement of conditions is recommended in order to obtain the highest quality crystals that can be grown. The quality of an X-ray structure determination is directly correlated with the size and the perfection of the crystalline samples; thus, refinement of conditions should always be a primary component of crystal growth. The improvement process is referred to as optimization, and it entails sequential, incremental changes in the chemical parameters that influence crystallization, such as pH, ionic strength and precipitant concentration, as well as physical parameters such as temperature, sample volume and overall methodology. It also includes the application of some unique procedures and approaches, and the addition of novel components such as detergents, ligands or other small molecules that may enhance nucleation or crystal development. Here, an attempt is made to provide guidance on how optimization might best be applied to crystal-growth problems, and what parameters and factors might most profitably be explored to accelerate and achieve success. PMID:25372810

Study of the In2O3 molecule in the free state and in the crystal

NASA Astrophysics Data System (ADS)

Kaplan, Ilya G.; Miranda, Ulises; Trakhtenberg, Leonid I.

2018-03-01

The nanomaterials based on the In2O3 molecule are widely used as catalysts and sensors among other applications. In the present study, we discuss the possibility of using nanoclusters of In2O3 as molecular photomotors. A comparative analysis of the electronic structure of the In2O3 molecule in the free state and in the crystal is performed. For the free In2O3 molecule the geometry of its lowest structures, V-shape and linear, was optimised at the CCSD(T) level, which is the most precise computational method applied up to date to study In2O3. Using experimental crystallographic data, we determined the geometry of In2O3 in the crystal. It has a zigzag, not symmetric structure and possesses a dipole moment with magnitude slightly smaller than that of the V-structure of the free molecule (the linear structure due to its symmetry has no dipole moment). According to the Natural Atomic population analysis, the chemical structure of the linear In2O3 can be represented as O = In-O-In = O; the V-shaped molecule has the similar double- and single-bond structure. The construction of nanoclusters from ´bricksʼ of In2O3 with geometry extracted from crystal (or nanoclusters extracted directly from crystal) and their use as photo-driven molecular motors are discussed.

Using light transmission to watch hydrogen diffuse

PubMed Central

Pálsson, Gunnar K.; Bliersbach, Andreas; Wolff, Max; Zamani, Atieh; Hjörvarsson, Björgvin

2012-01-01

Because of its light weight and small size, hydrogen exhibits one of the fastest diffusion rates in solid materials, comparable to the diffusion rate of liquid water molecules at room temperature. The diffusion rate is determined by an intricate combination of quantum effects and dynamic interplay with the displacement of host atoms that is still only partially understood. Here we present direct observations of the spatial and temporal changes in the diffusion-induced concentration profiles in a vanadium single crystal and we show that the results represent the experimental counterpart of the full time and spatial solution of Fick's diffusion equation. We validate the approach by determining the diffusion rate of hydrogen in a single crystal vanadium (001) film, with net diffusion in the [110] direction. PMID:22692535

Small Molecule Inhibitors That Selectively Block Dengue Virus Methyltransferase*

PubMed Central

Lim, Siew Pheng; Sonntag, Louis Sebastian; Noble, Christian; Nilar, Shahul H.; Ng, Ru Hui; Zou, Gang; Monaghan, Paul; Chung, Ka Yan; Dong, Hongping; Liu, Boping; Bodenreider, Christophe; Lee, Gladys; Ding, Mei; Chan, Wai Ling; Wang, Gang; Jian, Yap Li; Chao, Alexander Theodore; Lescar, Julien; Yin, Zheng; Vedananda, T. R.; Keller, Thomas H.; Shi, Pei-Yong

2011-01-01

Crystal structure analysis of Flavivirus methyltransferases uncovered a flavivirus-conserved cavity located next to the binding site for its cofactor, S-adenosyl-methionine (SAM). Chemical derivatization of S-adenosyl-homocysteine (SAH), the product inhibitor of the methylation reaction, with substituents that extend into the identified cavity, generated inhibitors that showed improved and selective activity against dengue virus methyltransferase (MTase), but not related human enzymes. Crystal structure of dengue virus MTase with a bound SAH derivative revealed that its N6-substituent bound in this cavity and induced conformation changes in residues lining the pocket. These findings demonstrate that one of the major hurdles for the development of methyltransferase-based therapeutics, namely selectivity for disease-related methyltransferases, can be overcome. PMID:21147775

Using light transmission to watch hydrogen diffuse

NASA Astrophysics Data System (ADS)

Pálsson, Gunnar K.; Bliersbach, Andreas; Wolff, Max; Zamani, Atieh; Hjörvarsson, Björgvin

2012-06-01

Because of its light weight and small size, hydrogen exhibits one of the fastest diffusion rates in solid materials, comparable to the diffusion rate of liquid water molecules at room temperature. The diffusion rate is determined by an intricate combination of quantum effects and dynamic interplay with the displacement of host atoms that is still only partially understood. Here we present direct observations of the spatial and temporal changes in the diffusion-induced concentration profiles in a vanadium single crystal and we show that the results represent the experimental counterpart of the full time and spatial solution of Fick's diffusion equation. We validate the approach by determining the diffusion rate of hydrogen in a single crystal vanadium (001) film, with net diffusion in the [110] direction.

Area laser crystallized LTPS TFTs with implanted contacts for active matrix OLED displays

NASA Astrophysics Data System (ADS)

Persidis, Efstathios; Baur, Holger; Pieralisi, Fabio; Schalberger, Patrick; Fruehauf, Norbert

2008-03-01

We have developed a four mask low temperature poly-Si (LTPS) TFT process for p- and n-channel devices. Our PECVD deposited amorphous silicon is recrystallized to polycrystalline silicon with single area excimer laser crystallization while formation of drain and source is carried out with self aligned ion beam implantation. We have investigated implantation parameters, suitability of various metallizations as well as laser activation and annealing procedures. To prove the potential capability of our devices, which are suitable for conventional and inverted OLEDs alike, we have produced several functional active matrix backplanes implementing different pixel circuits. Our active matrix backplane process has been customized to drive small molecules as well as polymers, regardless if top or bottom emitting.

Intermolecular Interactions and Electrostatic Properties of the [beta]-Hydroquinone Apohost: Implications for Supramolecular Chemistry

DOE Office of Scientific and Technical Information (OSTI.GOV)

Clausen, Henrik F.; Chen, Yu-Sheng; Jayatilaka, Dylan

2012-02-07

The crystal structure of the {beta}-polymorph of hydroquinone ({beta}-HQ), the apohost of a large family of clathrates, is reported with a specific focus on intermolecular interactions and the electrostatic nature of its cavity. Hirshfeld surface analysis reveals subtle close contacts between two interconnecting HQ networks, and the local packing and related close contacts were examined by breakdown of the fingerprint plot. An experimental multipole model containing anisotropic thermal parameters for hydrogen atoms has been successfully refined against 15(2) K single microcrystal synchrotron X-ray diffraction data. The experimental electron density model has been compared with a theoretical electron density calculated withmore » the molecule embedded in its own crystal field. Hirshfeld charges, interaction energies and the electrostatic potential calculated for both models are qualitatively in good agreement, but small differences in the electrostatic potential persist due to charge transfer from all hydrogen atoms to the oxygen atoms in the theoretical model. The electrostatic potential in the center of the cavity is positive, very shallow and highly symmetric, suggesting that the inclusion of polar molecules in the void will involve a balance between opposing effects. The electric field is by symmetry zero in the center of the cavity, increasing to a value of 0.0185 e/{angstrom}{sup 2} (0.27 V/{angstrom}) 1 {angstrom} along the 3-fold axis and 0.0105 e/{angstrom}{sup 2} (0.15 V/{angstrom}) 1 {angstrom} along the perpendicular direction. While these values are substantial in a macroscopic context, they are quite small for a molecular cavity and are not expected to strongly polarize a guest molecule.« less

Gentle, fast and effective crystal soaking by acoustic dispensing

PubMed Central

Ng, Jia Tsing; Talon, Romain; Nekrosiute, Karolina; Krojer, Tobias; Douangamath, Alice; Brandao-Neto, Jose; Pearce, Nicholas M.; von Delft, Frank

2017-01-01

The steady expansion in the capacity of modern beamlines for high-throughput data collection, enabled by increasing X-ray brightness, capacity of robotics and detector speeds, has pushed the bottleneck upstream towards sample preparation. Even in ligand-binding studies using crystal soaking, the experiment best able to exploit beamline capacity, a primary limitation is the need for gentle and nontrivial soaking regimens such as stepwise concentration increases, even for robust and well characterized crystals. Here, the use of acoustic droplet ejection for the soaking of protein crystals with small molecules is described, and it is shown that it is both gentle on crystals and allows very high throughput, with 1000 unique soaks easily performed in under 10 min. In addition to having very low compound consumption (tens of nanolitres per sample), the positional precision of acoustic droplet ejection enables the targeted placement of the compound/solvent away from crystals and towards drop edges, allowing gradual diffusion of solvent across the drop. This ensures both an improvement in the reproducibility of X-ray diffraction and increased solvent tolerance of the crystals, thus enabling higher effective compound-soaking concentrations. The technique is detailed here with examples from the protein target JMJD2D, a histone lysine demethylase with roles in cancer and the focus of active structure-based drug-design efforts. PMID:28291760

Investigation of ferroelectric liquid crystal orientation in the silica microcapillaries

NASA Astrophysics Data System (ADS)

Budaszewski, D.; Domański, A. W.; Woliński, T. R.

2013-05-01

In the paper we present our recent results concerning the orientation of ferroelectric liquid crystal molecules inside silica micro capillaries. We have infiltrated the silica micro capillaries with experimental ferroelectric liquid crystal material W-260K synthesized in the Military University of Technology. The infiltrated micro capillaries were observed under the polarization microscope while both a polarizer and an analyzer were crossed. The studies on the orientation of ferroelectric liquid crystal molecules may contribute to further studies on behavior of this group of liquid crystal materials inside photonic crystal fiber. The obtained results may lead to design of a new type of fast optical fiber sensors.

Modeling Structure and Dynamics of Protein Complexes with SAXS Profiles

PubMed Central

Schneidman-Duhovny, Dina; Hammel, Michal

2018-01-01

Small-angle X-ray scattering (SAXS) is an increasingly common and useful technique for structural characterization of molecules in solution. A SAXS experiment determines the scattering intensity of a molecule as a function of spatial frequency, termed SAXS profile. SAXS profiles can be utilized in a variety of molecular modeling applications, such as comparing solution and crystal structures, structural characterization of flexible proteins, assembly of multi-protein complexes, and modeling of missing regions in the high-resolution structure. Here, we describe protocols for modeling atomic structures based on SAXS profiles. The first protocol is for comparing solution and crystal structures including modeling of missing regions and determination of the oligomeric state. The second protocol performs multi-state modeling by finding a set of conformations and their weights that fit the SAXS profile starting from a single-input structure. The third protocol is for protein-protein docking based on the SAXS profile of the complex. We describe the underlying software, followed by demonstrating their application on interleukin 33 (IL33) with its primary receptor ST2 and DNA ligase IV-XRCC4 complex. PMID:29605933

Single crystal X-ray diffraction, spectroscopic and mass spectrometric studies of furanocoumarin peucedanin.

PubMed

Bartnik, Magdalena; Arczewska, Marta; Hoser, Anna A; Mroczek, Tomasz; Kamiński, Daniel M; Głowniak, Kazimierz; Gagoś, Mariusz; Woźniak, Krzysztof

2014-01-01

The structure of peucedanin, isolated from Peucedanum tauricum Bieb. (Apiaceae), has been established using single crystal X-ray diffraction. This furanocoumarin isolated from the light petroleum extract of P. tauricum fruits was characterized by high resolution EI-MS, sATR-FTIR and 2D NMR spectroscopic techniques. The EI-MS showed the typical fragmentation pattern of methoxyfuranocoumarins. Extensive 1D (1H and 13C) as well as 2D NMR data enabled complete assignment of the carbon atoms in the peucedanin molecule. The FTIR data confirms intermolecular hydrogen bonding between peucedanin molecules in polar solvents. Peucedanin crystallises in the R-3 space group from the trigonal system with one molecule in the asymmetric part of the unit cell. The crystal lattice of peucedanin consists of the molecules arranged in separate columns. They are related by two fold screw axes and centres of symmetry. Interestingly, peucedanin columns form two channels per unit cell with a diameter of 7.5angstrom going through the crystal lattice in the Z-direction. These channels are filled with disordered water molecules, which are surrounded by hydrophobic methyl groups and are located exactly at the centres of the channels. The peucedanin molecules are stacked in a single column with the opposite orientation of the neighbouring molecules. These results could be interesting in further application of this molecule, for example in biological tests of its activity.

Protein Crystals and their Growth

NASA Technical Reports Server (NTRS)

Chernov, A. A.

2004-01-01

Recent results on binding between protein molecules in crystal lattice, crystal-solution surface energy, elastic properties and strength and spontaneous crystal cracking are reviewed and discussed in the first half of this paper (Sea 2-4). In the second par&, some basic approaches to solubility of proteins are followed by overview on crystal nucleation and growth (Sec 5). It is argued that variability of mixing in batch crystallization may be a source for scattering of crystal number ultimately appearing in the batch. Frequency at which new molecules join crystal lattice is measured by kinetic coefficient and related to the observable crystal growth rate. Numerical criteria to discriminate diffusion and kinetic limited growth are discussed on this basis in Sec 7. In Sec 8, creation of defects is discussed with the emphasis on the role of impurities and convection on macromolecular crystal I;erfection.

Molecule diagram from earth-grown crystals

NASA Technical Reports Server (NTRS)

2004-01-01

Like many chemicals in the body, the three-dimensional structure of insulin is extremely complex. When grown on the ground, insulin crystals do not grow as large or as ordered as researchers desire--obscuring the blueprint of the insulin molecules.

Development and application of an exchange model for anisotropic water diffusion in the microporous MOF aluminum fumarate

NASA Astrophysics Data System (ADS)

Splith, Tobias; Fröhlich, Dominik; Henninger, Stefan K.; Stallmach, Frank

2018-06-01

Diffusion of water in aluminum fumarate was studied by means of pulsed field gradient (PFG) nuclear magnetic resonance (NMR). Due to water molecules exchanging between the intracrystalline anisotropic pore space and the isotropic intercrystalline void space the model of intracrystalline anisotropic diffusion fails to describe the experimental PFG NMR data at high observation times. Therefore, the two-site exchange model developed by Kärger is extended to the case of exchange between an anisotropic and an isotropic site. This extended exchange model is solved by numerical integration. It describes the experimental data very well and yields values for the intracrystalline diffusion coefficient and the mean residence times of the respective sites. Further PFG NMR studies were performed with coatings consisting of small aluminum fumarate crystals, which are used in adsorptive heat transformation applications. The diffusion coefficients of water in the small crystal coating are compared to the values expected from the extended two-site exchange model and from the model of long-range diffusion.

Small Molecules Engage Hot Spots through Cooperative Binding To Inhibit a Tight Protein-Protein Interaction.

PubMed

Liu, Degang; Xu, David; Liu, Min; Knabe, William Eric; Yuan, Cai; Zhou, Donghui; Huang, Mingdong; Meroueh, Samy O

2017-03-28

Protein-protein interactions drive every aspect of cell signaling, yet only a few small-molecule inhibitors of these interactions exist. Despite our ability to identify critical residues known as hot spots, little is known about how to effectively engage them to disrupt protein-protein interactions. Here, we take advantage of the ease of preparation and stability of pyrrolinone 1, a small-molecule inhibitor of the tight interaction between the urokinase receptor (uPAR) and its binding partner, the urokinase-type plasminogen activator uPA, to synthesize more than 40 derivatives and explore their effect on the protein-protein interaction. We report the crystal structure of uPAR bound to previously discovered pyrazole 3 and to pyrrolinone 12. While both 3 and 12 bind to uPAR and compete with a fluorescently labeled peptide probe, only 12 and its derivatives inhibit the full uPAR·uPA interaction. Compounds 3 and 12 mimic and engage different hot-spot residues on uPA and uPAR, respectively. Interestingly, 12 is involved in a π-cation interaction with Arg-53, which is not considered a hot spot. Explicit-solvent molecular dynamics simulations reveal that 3 and 12 exhibit dramatically different correlations of motion with residues on uPAR. Free energy calculations for the wild-type and mutant uPAR bound to uPA or 12 show that Arg-53 interacts with uPA or with 12 in a highly cooperative manner, thereby altering the contributions of hot spots to uPAR binding. The direct engagement of peripheral residues not considered hot spots through π-cation or salt-bridge interactions could provide new opportunities for enhanced small-molecule engagement of hot spots to disrupt challenging protein-protein interactions.

Molecular Probing of the HPV-16 E6 Protein Alpha Helix Binding Groove with Small Molecule Inhibitors

PubMed Central

Rietz, Anne; Petrov, Dino P.; Bartolowits, Matthew; DeSmet, Marsha; Davisson, V. Jo; Androphy, Elliot J.

2016-01-01

The human papillomavirus (HPV) HPV E6 protein has emerged as a central oncoprotein in HPV-associated cancers in which sustained expression is required for tumor progression. A majority of the E6 protein interactions within the human proteome use an alpha-helix groove interface for binding. The UBE3A/E6AP HECT domain ubiquitin ligase binds E6 at this helix-groove interface. This enables formation of a trimeric complex with p53, resulting in destruction of this tumor suppressor. While recent x-ray crystal structures are useful, examples of small molecule probes that can modulate protein interactions at this interface are limited. To develop insights useful for potential structure-based design of ligands for HPV E6, a series of 2,6-disubstituted benzopyranones were prepared and tested as competitive antagonists of E6-E6AP helix-groove interactions. These small molecule probes were used in both binding and functional assays to evaluate recognition features of the E6 protein. Evidence for an ionic functional group interaction within the helix groove was implicated by the structure-activity among the highest affinity ligands. The molecular topographies of these protein-ligand interactions were evaluated by comparing the binding and activities of single amino acid E6 mutants with the results of molecular dynamic simulations. A group of arginine residues that form a rim-cap over the E6 helix groove offer compensatory roles in binding and recognition of the small molecule probes. The flexibility and impact on the overall helix-groove shape dictated by these residues offer new insights for structure-based targeting of HPV E6. PMID:26915086

Remarkable Enhancement of the Hole Mobility in Several Organic Small-Molecules, Polymers, and Small-Molecule:Polymer Blend Transistors by Simple Admixing of the Lewis Acid p-Dopant B(C6F5)3.

PubMed

Panidi, Julianna; Paterson, Alexandra F; Khim, Dongyoon; Fei, Zhuping; Han, Yang; Tsetseris, Leonidas; Vourlias, George; Patsalas, Panos A; Heeney, Martin; Anthopoulos, Thomas D

2018-01-01

Improving the charge carrier mobility of solution-processable organic semiconductors is critical for the development of advanced organic thin-film transistors and their application in the emerging sector of printed electronics. Here, a simple method is reported for enhancing the hole mobility in a wide range of organic semiconductors, including small-molecules, polymers, and small-molecule:polymer blends, with the latter systems exhibiting the highest mobility. The method is simple and relies on admixing of the molecular Lewis acid B(C 6 F 5 ) 3 in the semiconductor formulation prior to solution deposition. Two prototypical semiconductors where B(C 6 F 5 ) 3 is shown to have a remarkable impact are the blends of 2,8-difluoro-5,11-bis(triethylsilylethynyl)anthradithiophene:poly(triarylamine) (diF-TESADT:PTAA) and 2,7-dioctyl[1]-benzothieno[3,2-b][1]benzothiophene:poly(indacenodithiophene-co-benzothiadiazole) (C8-BTBT:C16-IDTBT), for which hole mobilities of 8 and 11 cm 2 V -1 s -1 , respectively, are obtained. Doping of the 6,13-bis(triisopropylsilylethynyl)pentacene:PTAA blend with B(C 6 F 5 ) 3 is also shown to increase the maximum hole mobility to 3.7 cm 2 V -1 s -1 . Analysis of the single and multicomponent materials reveals that B(C 6 F 5 ) 3 plays a dual role, first acting as an efficient p-dopant, and secondly as a microstructure modifier. Semiconductors that undergo simultaneous p-doping and dopant-induced long-range crystallization are found to consistently outperform transistors based on the pristine materials. Our work underscores Lewis acid doping as a generic strategy towards high performance printed organic microelectronics.

Identification of antipsychotic drug fluspirilene as a potential p53-MDM2 inhibitor: a combined computational and experimental study

NASA Astrophysics Data System (ADS)

Patil, Sachin P.; Pacitti, Michael F.; Gilroy, Kevin S.; Ruggiero, John C.; Griffin, Jonathan D.; Butera, Joseph J.; Notarfrancesco, Joseph M.; Tran, Shawn; Stoddart, John W.

2015-02-01

The inhibition of tumor suppressor p53 protein due to its direct interaction with oncogenic murine double minute 2 (MDM2) protein, plays a central role in almost 50 % of all human tumor cells. Therefore, pharmacological inhibition of the p53-binding pocket on MDM2, leading to p53 activation, presents an important therapeutic target against these cancers expressing wild-type p53. In this context, the present study utilized an integrated virtual and experimental screening approach to screen a database of approved drugs for potential p53-MDM2 interaction inhibitors. Specifically, using an ensemble rigid-receptor docking approach with four MDM2 protein crystal structures, six drug molecules were identified as possible p53-MDM2 inhibitors. These drug molecules were then subjected to further molecular modeling investigation through flexible-receptor docking followed by Prime/MM-GBSA binding energy analysis. These studies identified fluspirilene, an approved antipsychotic drug, as a top hit with MDM2 binding mode and energy similar to that of a native MDM2 crystal ligand. The molecular dynamics simulations suggested stable binding of fluspirilene to the p53-binding pocket on MDM2 protein. The experimental testing of fluspirilene showed significant growth inhibition of human colon tumor cells in a p53-dependent manner. Fluspirilene also inhibited growth of several other human tumor cell lines in the NCI60 cell line panel. Taken together, these computational and experimental data suggest a potentially novel role of fluspirilene in inhibiting the p53-MDM2 interaction. It is noteworthy here that fluspirilene has a long history of safe human use, thus presenting immediate clinical potential as a cancer therapeutic. Furthermore, fluspirilene could also serve as a structurally-novel lead molecule for the development of more potent, small-molecule p53-MDM2 inhibitors against several types of cancer. Importantly, the combined computational and experimental screening protocol presented in this study may also prove useful for screening other commercially-available compound databases for identification of novel, small molecule p53-MDM2 inhibitors.

Supramolecular macrocycles reversibly assembled by Te…O chalcogen bonding

PubMed Central

Ho, Peter C.; Szydlowski, Patrick; Sinclair, Jocelyn; Elder, Philip J. W.; Kübel, Joachim; Gendy, Chris; Lee, Lucia Myongwon; Jenkins, Hilary; Britten, James F.; Morim, Derek R.; Vargas-Baca, Ignacio

2016-01-01

Organic molecules with heavy main-group elements frequently form supramolecular links to electron-rich centres. One particular case of such interactions is halogen bonding. Most studies of this phenomenon have been concerned with either dimers or infinitely extended structures (polymers and lattices) but well-defined cyclic structures remain elusive. Here we present oligomeric aggregates of heterocycles that are linked by chalcogen-centered interactions and behave as genuine macrocyclic species. The molecules of 3-methyl-5-phenyl-1,2-tellurazole 2-oxide assemble a variety of supramolecular aggregates that includes cyclic tetramers and hexamers, as well as a helical polymer. In all these aggregates, the building blocks are connected by Te…O–N bridges. Nuclear magnetic resonance spectroscopic experiments demonstrate that the two types of annular aggregates are persistent in solution. These self-assembled structures form coordination complexes with transition-metal ions, act as fullerene receptors and host small molecules in a crystal. PMID:27090355

Crystal structures and intermolecular interactions of two novel antioxidant triazolyl-benzimidazole compounds

DOE Office of Scientific and Technical Information (OSTI.GOV)

Karayel, A., E-mail: matchlessjimmy@163.com, E-mail: yccaoh@hotmail.com; Özbey, S.; Ayhan-Kılcıgil, G.

2015-12-15

The crystal structures of 5-(2-(p-chlorophenylbenzimidazol-1-yl-methyl)-4-(3-fluorophenyl)-2, 4-dihydro-[1,2,4]-triazole-3-thione (G6C) and 5-(2-(p-chlorophenylbenzimidazol-1-yl-methyl)-4-(2-methylphenyl)-2, 4-dihydro-[1,2,4]-triazole-3-thione (G4C) have been determined by single-crystal X-ray diffraction. Benzimidazole ring systems in both molecules are planar. The triazole part is almost perpendicular to the phenyl and the benzimidazole parts of the molecules in order to avoid steric interactions between the rings. The crystal structures are stabilized by intermolecular hydrogen bonds between the amino group of the triazole and the nitrogen atom of benzimidazole of a neighboring molecule.

Crystal structure of the co-crystal fac-tri-aqua-tris(thio-cyanato-κN)iron(III)-2,3-di-methyl-pyrazine (1/3).

PubMed

Kucheriv, Olesia I; Shylin, Sergii I; Ilina, Tetiana A; Dechert, Sebastian; Gural'skiy, Il'ya A

2015-04-01

In the crystal of the title compound, [Fe(NCS)3(H2O)3]·3C6H8N2, the Fe(III) cation is located on a threefold rotation axis and is coordinated by three N atoms of the thiocyanate anions and three water mol-ecules in a fac arrangement, forming a slightly distorted N3O3 octa-hedron. Stabilization within the crystal structure is provided by O-H⋯N hydrogen bonds; the H atoms from coordinating water mol-ecules act as donors to the N atoms of guest 2,3-di-methyl-pyrazine mol-ecules, leading to a three-dimensional supra-molecular framework.

Apparatus for detecting and recognizing analytes based on their crystallization patterns

DOEpatents

Morozov, Victor; Bailey, Charles L.; Vsevolodov, Nikolai N.; Elliott, Adam

2010-12-14

The invention contemplates apparatuses for recognition of proteins and other biological molecules by imaging morphology, size and distribution of crystalline and amorphous dry residues in droplets (further referred to as "crystallization patterns") containing predetermined amount of certain crystal-forming organic compounds (reporters) to which protein to be analyzed is added. Changes in the crystallization patterns of a number of amino-acids can be used as a "signature" of a protein added. Also, changes in the crystallization patterns, as well as the character of such changes, can be used as recognition elements in analysis of protein molecules.

Flow-Directed Crystallization for Printed Electronics.

PubMed

Qu, Ge; Kwok, Justin J; Diao, Ying

2016-12-20

The solution printability of organic semiconductors (OSCs) represents a distinct advantage for materials processing, enabling low-cost, high-throughput, and energy-efficient manufacturing with new form factors that are flexible, stretchable, and transparent. While the electronic performance of OSCs is not comparable to that of crystalline silicon, the solution processability of OSCs allows them to complement silicon by tackling challenging aspects for conventional photolithography, such as large-area electronics manufacturing. Despite this, controlling the highly nonequilibrium morphology evolution during OSC printing remains a challenge, hindering the achievement of high electronic device performance and the elucidation of structure-property relationships. Many elegant morphological control methodologies have been developed in recent years including molecular design and novel processing approaches, but few have utilized fluid flow to control morphology in OSC thin films. In this Account, we discuss flow-directed crystallization as an effective strategy for controlling the crystallization kinetics during printing of small molecule and polymer semiconductors. Introducing the concept of flow-directed crystallization to the field of printed electronics is inspired by recent advances in pharmaceutical manufacturing and flow processing of flexible-chain polymers. Although flow-induced crystallization is well studied in these areas, previous findings may not apply directly to the field of printed electronics where the molecular structures (i.e., rigid π-conjugated backbone decorated with flexible side chains) and the intermolecular interactions (i.e., π-π interactions, quadrupole interactions) of OSCs differ substantially from those of pharmaceuticals or flexible-chain polymers. Another critical difference is the important role of solvent evaporation in open systems, which defines the flow characteristics and determines the crystallization kinetics and pathways. In other words, flow-induced crystallization is intimately coupled with the mass transport processes driven by solvent evaporation during printing. In this Account, we will highlight these distinctions of flow-directed crystallization for printed electronics. In the context of solution printing of OSCs, the key issue that flow-directed crystallization addresses is the kinetics mismatch between crystallization and various transport processes during printing. We show that engineering fluid flows can tune the kinetics of OSC crystallization by expediting the nucleation and crystal growth processes, significantly enhancing thin film morphology and device performance. For small molecule semiconductors, nucleation can be enhanced and patterned by directing the evaporative flux via contact line engineering, and defective crystal growth can be alleviated by enhancing mass transport to yield significantly improved coherence length and reduced grain boundaries. For conjugated polymers, extensional and shear flow can expedite nucleation through flow-induced conformation change, facilitating the control of microphase separation, degree of crystallinity, domain alignment, and percolation. Although the nascent concept of flow-directed solution printing has not yet been widely adopted in the field of printed electronics, we anticipate that it can serve as a platform technology in the near future for improving device performance and for systematically tuning thin film morphology to construct structure-property relationships. From a fundamental perspective, it is imperative to develop a better understanding of the effects of fluid flow and mass transport on OSC crystallization as these processes are ubiquitous across all solution processing techniques and can critically impact charge transport properties.

A co-crystal between benzene and ethane: a potential evaporite material for Saturn’s moon Titan

PubMed Central

Maynard-Casely, Helen E.; Hodyss, Robert; Cable, Morgan L.; Vu, Tuan Hoang; Rahm, Martin

2016-01-01

Using synchrotron X-ray powder diffraction, the structure of a co-crystal between benzene and ethane formed in situ at cryogenic conditions has been determined, and validated using dispersion-corrected density functional theory calculations. The structure comprises a lattice of benzene molecules hosting ethane molecules within channels. Similarity between the intermolecular interactions found in the co-crystal and in pure benzene indicate that the C—H⋯π network of benzene is maintained in the co-crystal, however, this expands to accommodate the guest ethane molecules. The co-crystal has a 3:1 benzene:ethane stoichiometry and is described in the space group with a = 15.977 (1) Å and c = 5.581 (1) Å at 90 K, with a density of 1.067 g cm−3. The conditions under which this co-crystal forms identify it is a potential that forms from evaporation of Saturn’s moon Titan’s lakes, an evaporite material. PMID:27158505

The production and crystallization of the human leukocyte antigen class II molecules HLA-DQ2 and HLA-DQ8 complexed with deamidated gliadin peptides implicated in coeliac disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Henderson, Kate N.; Reid, Hugh H.; Borg, Natalie A.

2007-12-01

The production and crystallization of human leukocyte antigen class II molecules HLA-DQ2 and HLA-DQ8 in complex with deamidated gliadin peptides is reported. Crystals of HLA-DQ2{sup PQPELPYPQ} diffracted to 3.9 Å, while the HLA-DQ8{sup EGSFQPSQE} crystals diffracted to 2.1 Å, allowing structure determination by molecular replacement. The major histocompatibility complex (MHC) class II molecules HLA-DQ2 and HLA-DQ8 are key risk factors in coeliac disease, as they bind deamidated gluten peptides that are subsequently recognized by CD4{sup +} T cells. Here, the production and crystallization of both HLA-DQ2 and HLA-DQ8 in complex with the deamidated gliadin peptides DQ2 α-I (PQPELPYPQ) and DQ8more » α-I (EGSFQPSQE), respectively, are reported.« less

Modern Possibilities for Calculating Some Properties of Molecules and Crystals from the Experimental Electron Density

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stash, A.I.; Tsirelson, V.G.

2005-03-01

Methods for calculating some properties of molecules and crystals from the electron density reconstructed from a precise X-ray diffraction experiment using the multipole model are considered. These properties include, on the one hand, the characteristics of the electron density and the inner-crystal electrostatic field and, on the other hand, the local electronic energies (kinetic, potential, total), the exchange energy density, the electron-pair localization function, the localized-orbital locator, the effective crystal potential, and others. It is shown that the integration of these characteristics over pseudoatomic volumes bounded by the surfaces of the zero flux of the electron density gradient makes itmore » possible to characterize directly from an experiment the properties of molecules and crystals in terms of the atomic contributions. The computer program WinXPRO2004, realizing these possibilities, is briefly described.« less

Discovery of External Modulators of the Fe-Fe Hydrogenase Enzyme in Clostridium acetobutylicum

DTIC Science & Technology

2015-02-01

I-TASSER (orange) with the experimental structure ( PDB ID: 1FEH, blue) ................5 Fig. 4 Putative docking site 1 of Fd (blue) to Fe-only...dock small molecules to a homologous structure of the C. acet. HydA from Clostridium pasteurianum (C. past.; protein data bank [ PDB ] id: 1FEH1) (Fig. 2...Agreement among these models was excellent, as well as agreement with the C. past. crystal structure ( PDB id: 1FEH1). Alignment and comparison with the

Microgravity

NASA Image and Video Library

2001-01-24

Vapor Diffusion Apparatus (VDA and VDA-2) was developed by the University of Alabama in Birmingham for NASA's Marshall Space Flight Center. In the original VDA, a protein solution and a precipitant are extruded by two plungers onto the tip of a small syringe and allowed to evaporate, raising the concentration and prompting protein molecules to crystallize. In the VDA-2 version, a third plunger was added to mix the two solutions before returning the mix to the syringe tip. The principal investigator is Dr. Larry Delucas of the University of Alabama in Birmingham

Microgravity

NASA Image and Video Library

2001-01-24

Vapor Diffusion Apparatus (VDA-2) was developed by the University of Alabama in Birmingham for NASA's Marshall Space Flight Center. In the original VDA, a protein solution and a precipitant are extruded by two plungers onto the tip of a small syringe and allowed to evaporate, raising the concentration and prompting protein molecules to crystallize. In the VDA-2 version, a third plunger was added to mix the two solutions before returning the mix to the syringe tip. The principal investigator is Dr. Larry Delucas of the University of Alabama in Birmingham.

Structure-based design, synthesis and crystallization of 2-arylquinazolines as lipid pocket ligands of p38α MAPK

PubMed Central

Bührmann, Mike; Wiedemann, Bianca M.; Müller, Matthias P.; Hardick, Julia; Ecke, Maria

2017-01-01

In protein kinase research, identifying and addressing small molecule binding sites other than the highly conserved ATP-pocket are of intense interest because this line of investigation extends our understanding of kinase function beyond the catalytic phosphotransfer. Such alternative binding sites may be involved in altering the activation state through subtle conformational changes, control cellular enzyme localization, or in mediating and disrupting protein-protein interactions. Small organic molecules that target these less conserved regions might serve as tools for chemical biology research and to probe alternative strategies in targeting protein kinases in disease settings. Here, we present the structure-based design and synthesis of a focused library of 2-arylquinazoline derivatives to target the lipophilic C-terminal binding pocket in p38α MAPK, for which a clear biological function has yet to be identified. The interactions of the ligands with p38α MAPK was analyzed by SPR measurements and validated by protein X-ray crystallography. PMID:28892510

Crystallographic structure of a small molecule SIRT1 activator-enzyme complex

NASA Astrophysics Data System (ADS)

Dai, Han; Case, April W.; Riera, Thomas V.; Considine, Thomas; Lee, Jessica E.; Hamuro, Yoshitomo; Zhao, Huizhen; Jiang, Yong; Sweitzer, Sharon M.; Pietrak, Beth; Schwartz, Benjamin; Blum, Charles A.; Disch, Jeremy S.; Caldwell, Richard; Szczepankiewicz, Bruce; Oalmann, Christopher; Yee Ng, Pui; White, Brian H.; Casaubon, Rebecca; Narayan, Radha; Koppetsch, Karsten; Bourbonais, Francis; Wu, Bo; Wang, Junfeng; Qian, Dongming; Jiang, Fan; Mao, Cheney; Wang, Minghui; Hu, Erding; Wu, Joe C.; Perni, Robert B.; Vlasuk, George P.; Ellis, James L.

2015-07-01

SIRT1, the founding member of the mammalian family of seven NAD+-dependent sirtuins, is composed of 747 amino acids forming a catalytic domain and extended N- and C-terminal regions. We report the design and characterization of an engineered human SIRT1 construct (mini-hSIRT1) containing the minimal structural elements required for lysine deacetylation and catalytic activation by small molecule sirtuin-activating compounds (STACs). Using this construct, we solved the crystal structure of a mini-hSIRT1-STAC complex, which revealed the STAC-binding site within the N-terminal domain of hSIRT1. Together with hydrogen-deuterium exchange mass spectrometry (HDX-MS) and site-directed mutagenesis using full-length hSIRT1, these data establish a specific STAC-binding site and identify key intermolecular interactions with hSIRT1. The determination of the interface governing the binding of STACs with human SIRT1 facilitates greater understanding of STAC activation of this enzyme, which holds significant promise as a therapeutic target for multiple human diseases.

Reducing dynamic disorder in small-molecule organic semiconductors by suppressing large-amplitude thermal motions

PubMed Central

Illig, Steffen; Eggeman, Alexander S.; Troisi, Alessandro; Jiang, Lang; Warwick, Chris; Nikolka, Mark; Schweicher, Guillaume; Yeates, Stephen G.; Henri Geerts, Yves; Anthony, John E.; Sirringhaus, Henning

2016-01-01

Thermal vibrations and the dynamic disorder they create can detrimentally affect the transport properties of van der Waals bonded molecular semiconductors. The low-energy nature of these vibrations makes it difficult to access them experimentally, which is why we still lack clear molecular design rules to control and reduce dynamic disorder. In this study we discuss the promising organic semiconductors rubrene, 2,7-dioctyl[1]benzothieno[3,2-b][1]benzothio-phene and 2,9-di-decyl-dinaphtho-[2,3-b:20,30-f]-thieno-[3,2-b]-thiophene in terms of an exceptionally low degree of dynamic disorder. In particular, we analyse diffuse scattering in transmission electron microscopy, to show that small molecules that have their side chains attached along the long axis of their conjugated core are better encapsulated in their crystal structure, which helps reduce large-amplitude thermal motions. Our work provides a general strategy for the design of new classes of very high mobility organic semiconductors with a low degree of dynamic disorder. PMID:26898754

Structural basis of substrate discrimination and integrin binding by autotaxin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hausmann, Jens; Kamtekar, Satwik; Christodoulou, Evangelos

2013-09-25

Autotaxin (ATX, also known as ectonucleotide pyrophosphatase/phosphodiesterase-2, ENPP2) is a secreted lysophospholipase D that generates the lipid mediator lysophosphatidic acid (LPA), a mitogen and chemoattractant for many cell types. ATX-LPA signaling is involved in various pathologies including tumor progression and inflammation. However, the molecular basis of substrate recognition and catalysis by ATX and the mechanism by which it interacts with target cells are unclear. Here, we present the crystal structure of ATX, alone and in complex with a small-molecule inhibitor. We have identified a hydrophobic lipid-binding pocket and mapped key residues for catalysis and selection between nucleotide and phospholipid substrates.more » We have shown that ATX interacts with cell-surface integrins through its N-terminal somatomedin B-like domains, using an atypical mechanism. Our results define determinants of substrate discrimination by the ENPP family, suggest how ATX promotes localized LPA signaling and suggest new approaches for targeting ATX with small-molecule therapeutic agents.« less

Kinetics of nucleation and crystallization in poly(e-caprolactone) (PCL)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhuravlev, Evgeny; Schmelzer, Jurn; Wunderlich, Bernhard

2011-01-01

The recently developed differential fast scanning calorimetry (DFSC) is used for a new look at the crystal growth of poly(3-caprolactone) (PCL) from 185 K, below the glass transition temperature, to 330 K, close to the equilibrium melting temperature. The DFSC allows temperature control of the sample and determination of its heat capacity using heating rates from 50 to 50,000 K/s. The crystal nucleation and crystallization halftimes were determined simultaneously. The obtained halftimes cover a range from 3 102 s (nucleation at 215 K) to 3 109 s (crystallization at 185 K). After attempting to analyze the experiments with the classicalmore » nucleation and growth model, developed for systems consisting of small molecules, a new methodology is described which addresses the specific problems of crystallization of flexible linear macromolecules. The key problems which are attempted to be resolved concern the differences between the structures of the various entities identified and their specific role in the mechanism of growth. The structures range from configurations having practically unmeasurable latent heats of ordering (nuclei) to being clearly-recognizable, ordered species with rather sharp disordering endotherms in the temperature range from the glass transition to equilibrium melting for increasingly perfect and larger crystals. The mechanisms and kinetics of growth involve also a detailed understanding of the interaction with the surrounding rigid-amorphous fraction (RAF) in dependence of crystal size and perfection.« less

Toward Fully in Silico Melting Point Prediction Using Molecular Simulations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Y; Maginn, EJ

2013-03-01

Melting point is one of the most fundamental and practically important properties of a compound. Molecular computation of melting points. However, all of these methods simulation methods have been developed for the accurate need an experimental crystal structure as input, which means that such calculations are not really predictive since the melting point can be measured easily in experiments once a crystal structure is known. On the other hand, crystal structure prediction (CSP) has become an active field and significant progress has been made, although challenges still exist. One of the main challenges is the existence of many crystal structuresmore » (polymorphs) that are very close in energy. Thermal effects and kinetic factors make the situation even more complicated, such that it is still not trivial to predict experimental crystal structures. In this work, we exploit the fact that free energy differences are often small between crystal structures. We show that accurate melting point predictions can be made by using a reasonable crystal structure from CSP as a starting point for a free energy-based melting point calculation. The key is that most crystal structures predicted by CSP have free energies that are close to that of the experimental structure. The proposed method was tested on two rigid molecules and the results suggest that a fully in silico melting point prediction method is possible.« less

New simulation model of multicomponent crystal growth and inhibition.

PubMed

Wathen, Brent; Kuiper, Michael; Walker, Virginia; Jia, Zongchao

2004-04-02

We review a novel computational model for the study of crystal structures both on their own and in conjunction with inhibitor molecules. The model advances existing Monte Carlo (MC) simulation techniques by extending them from modeling 3D crystal surface patches to modeling entire 3D crystals, and by including the use of "complex" multicomponent molecules within the simulations. These advances makes it possible to incorporate the 3D shape and non-uniform surface properties of inhibitors into simulations, and to study what effect these inhibitor properties have on the growth of whole crystals containing up to tens of millions of molecules. The application of this extended MC model to the study of antifreeze proteins (AFPs) and their effects on ice formation is reported, including the success of the technique in achieving AFP-induced ice-growth inhibition with concurrent changes to ice morphology that mimic experimental results. Simulations of ice-growth inhibition suggest that the degree of inhibition afforded by an AFP is a function of its ice-binding position relative to the underlying anisotropic growth pattern of ice. This extended MC technique is applicable to other crystal and crystal-inhibitor systems, including more complex crystal systems such as clathrates.

Solvent effects on the crystal growth structure and morphology of the pharmaceutical dirithromycin

NASA Astrophysics Data System (ADS)

Wang, Yuan; Liang, Zuozhong

2017-12-01

Solvent effects on the crystal structure and morphology of pharmaceutical dirithromycin molecules were systematically investigated using both experimental crystallization and theoretical simulation. Dirithromycin is one of the new generation of macrolide antibiotics with two polymorphic forms (Form I and Form II) and many solvate forms. Herein, six solvates of the dirithromycin, including acetonitrile, acetonitrile/water, acetone, 1-propanol, N,N-dimethylformamide (DMF) and cyclohexane, were studied. Experimentally, we crystallized the dirithromycin molecules in different solvents by the solvent evaporating method and measured the crystal structures with the X-ray diffraction (XRD). We compared these crystal structures of dirithromycin solvates and analyzed the solvent property-determined structure evolution. The solvents have a strong interaction with the dirithromycin molecule due to the formation of inter-molecular interactions (such as the hydrogen bonding and close contacts (sum of vdW radii)). Theoretically, we calculated the ideal crystal habit based on the solvated structures with the attachment growth (AE) model. The predicted morphologies and aspect ratios of dirithromycin solvates agree well with the experimental results. This work could be helpful to better understand the structure and morphology evolution of solvates controlled by solvents and guide the crystallization of active pharmaceutical ingredients in the pharmaceutical industry.

A small molecule targeting ALK1 prevents Notch cooperativity and inhibits functional angiogenesis.

PubMed

Kerr, Georgina; Sheldon, Helen; Chaikuad, Apirat; Alfano, Ivan; von Delft, Frank; Bullock, Alex N; Harris, Adrian L

2015-04-01

Activin receptor-like kinase 1 (ALK1, encoded by the gene ACVRL1) is a type I BMP/TGF-β receptor that mediates signalling in endothelial cells via phosphorylation of SMAD1/5/8. During angiogenesis, sprouting endothelial cells specialise into tip cells and stalk cells. ALK1 synergises with Notch in stalk cells to induce expression of the Notch targets HEY1 and HEY2 and thereby represses tip cell formation and angiogenic sprouting. The ALK1-Fc soluble protein fusion has entered clinic trials as a therapeutic strategy to sequester the high-affinity extracellular ligand BMP9. Here, we determined the crystal structure of the ALK1 intracellular kinase domain and explored the effects of a small molecule kinase inhibitor K02288 on angiogenesis. K02288 inhibited BMP9-induced phosphorylation of SMAD1/5/8 in human umbilical vein endothelial cells to reduce both the SMAD and the Notch-dependent transcriptional responses. In endothelial sprouting assays, K02288 treatment induced a hypersprouting phenotype reminiscent of Notch inhibition. Furthermore, K02288 caused dysfunctional vessel formation in a chick chorioallantoic membrane assay of angiogenesis. Such activity may be advantageous for small molecule inhibitors currently in preclinical development for specific BMP gain of function conditions, including diffuse intrinsic pontine glioma and fibrodysplasia ossificans progressiva, as well as more generally for other applications in tumour biology.

Improved ligand geometries in crystallographic refinement using AFITT in PHENIX

DOE PAGES

Janowski, Pawel A.; Moriarty, Nigel W.; Kelley, Brian P.; ...

2016-08-31

Modern crystal structure refinement programs rely on geometry restraints to overcome the challenge of a low data-to-parameter ratio. While the classical Engh and Huber restraints work well for standard amino-acid residues, the chemical complexity of small-molecule ligands presents a particular challenge. Most current approaches either limit ligand restraints to those that can be readily described in the Crystallographic Information File (CIF) format, thus sacrificing chemical flexibility and energetic accuracy, or they employ protocols that substantially lengthen the refinement time, potentially hindering rapid automated refinement workflows.PHENIX–AFITTrefinement uses a full molecular-mechanics force field for user-selected small-molecule ligands during refinement, eliminating the potentiallymore » difficult problem of finding or generating high-quality geometry restraints. It is fully integrated with a standard refinement protocol and requires practically no additional steps from the user, making it ideal for high-throughput workflows.PHENIX–AFITTrefinements also handle multiple ligands in a single model, alternate conformations and covalently bound ligands. Here, the results of combiningAFITTand thePHENIXsoftware suite on a data set of 189 protein–ligand PDB structures are presented. Refinements usingPHENIX–AFITTsignificantly reduce ligand conformational energy and lead to improved geometries without detriment to the fit to the experimental data. Finally, for the data presented,PHENIX–AFITTrefinements result in more chemically accurate models for small-molecule ligands.« less

Co(II)-doped MOF-5 nano/microcrystals: Solvatochromic behaviour, sensing solvent molecules and gas sorption property

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yang, Ji-Min; School of Chemistry and Chemical Engineering, Linyi University, Linyi 276005; Liu, Qing

2014-10-15

Co(II)-doped MOF-5 nano/microcrystals with controllable morphology and size were successfully obtained by solvothermal method. The products were characterized by powder X-ray diffraction (PXRD), energy dispersive spectrometry (EDS), field emission scanning electron microscopy (FESEM), thermogravimetric analysis (TGA), inductively coupled plasma optical emission spectrometer (ICP-OES), elemental analysis, UV–vis and infrared (IR) spectroscopy. The factors influencing the crystal morphology and size were investigated. The gas sorption measurements reveal that highly crystalline particles have large Langmuir surface area. It was found that the Co(II)-doped MOF-5 shows enhanced hydrostability and the sorption profiles of the Co(II)-doped MOF-5 nano/microcrystals are dependent on the morphology and sizemore » of the particles. Porous Co(II)-doped MOF-5 is stable upon the removal of guest molecules and exhibits different colour with accommodating different solvent molecule, which means that it can act as solvatochromic sensing materials for recognition of solvent molecules. - Graphical abstract: Co(II)-doped MOF-5 nano/microcrystals with different shapes and sizes were synthesized by a facile hydrothermal method, which not only enhance gas sorption properties and structural stability of MOFs towards moisture, but also act as new sensing materials for sensing small molecules. - Highlights: • Co(II)-doped MOF-5 nano/microcrystals with controllable morphology and size were obtained. • Co(II)-doped MOF-5 nano/microcrystals enhance the structural stability towards moisture. • Co(II)-doped MOF-5 can act as new sensing material for sensing small molecules.« less

Porous framework of T{sub 2}[Fe(CN){sub 6}].xH{sub 2}O with T=Co, Ni, Cu, Zn, and H{sub 2} storage

DOE Office of Scientific and Technical Information (OSTI.GOV)

Avila, M.; Reguera, L.; Rodriguez-Hernandez, J.

2008-11-15

The materials under study were prepared from aqueous solutions of ferrocyanic acid and salts of the involved transition metals and their crystal structure solved and refined from X-ray powder diffraction data. Complementary information from thermogravimetric, infrared and Moessbauer data was also used for the structural study. Three different crystal structures were found: hexagonal (P-3) for Zn with the zinc atom coordinated to three N ends of CN groups plus a water molecule, cubic (Pm-3m) for Ni and Cu, and monoclinic (P2{sub 1}/m) for Co. For Ni and Cu the obtained solids have an open channel framework related to 50% ofmore » vacancies for the building unit, [Fe(CN){sub 6}]. In the as-synthesized material the framework free volume is occupied by coordinated and hydrogen-bonded water molecules. These of hexacyanoferrates (II) have received certain attention as prototype of materials for the hydrogen storage. In the anhydrous phase of Ni and Cu, 50% of the metal (T) coordination sites, located at the cavities surface, will be available to interact with the hydrogen molecule. However, when the crystal waters are removed the porous frameworks collapse as it is suggested by H{sub 2} and CO{sub 2} adsorption data. For Co, a structure of stacked layers was found where the cobalt atoms have both tetrahedral and octahedral coordination. The layers remain together through a network of hydrogen-bonding interactions between coordinated and weakly bonded water molecules. No H{sub 2} adsorption was observed in the anhydrous phase of Co. For Zn, the porous framework remains stable on the water removal but with a system of narrow channels and a small available volume, also inaccessible to H{sub 2}. - Graphical abstract: Structure of stacked layers for CO{sub 2}[Fe(CN){sub 6}].xH{sub 2}O.« less

Machine learning and docking models for Mycobacterium tuberculosis topoisomerase I.

PubMed

Ekins, Sean; Godbole, Adwait Anand; Kéri, György; Orfi, Lászlo; Pato, János; Bhat, Rajeshwari Subray; Verma, Rinkee; Bradley, Erin K; Nagaraja, Valakunja

2017-03-01

There is a shortage of compounds that are directed towards new targets apart from those targeted by the FDA approved drugs used against Mycobacterium tuberculosis. Topoisomerase I (Mttopo I) is an essential mycobacterial enzyme and a promising target in this regard. However, it suffers from a shortage of known inhibitors. We have previously used computational approaches such as homology modeling and docking to propose 38 FDA approved drugs for testing and identified several active molecules. To follow on from this, we now describe the in vitro testing of a library of 639 compounds. These data were used to create machine learning models for Mttopo I which were further validated. The combined Mttopo I Bayesian model had a 5 fold cross validation receiver operator characteristic of 0.74 and sensitivity, specificity and concordance values above 0.76 and was used to select commercially available compounds for testing in vitro. The recently described crystal structure of Mttopo I was also compared with the previously described homology model and then used to dock the Mttopo I actives norclomipramine and imipramine. In summary, we describe our efforts to identify small molecule inhibitors of Mttopo I using a combination of machine learning modeling and docking studies in conjunction with screening of the selected molecules for enzyme inhibition. We demonstrate the experimental inhibition of Mttopo I by small molecule inhibitors and show that the enzyme can be readily targeted for lead molecule development. Copyright © 2017 Elsevier Ltd. All rights reserved.

Reading PDB: perception of molecules from 3D atomic coordinates.

PubMed

Urbaczek, Sascha; Kolodzik, Adrian; Groth, Inken; Heuser, Stefan; Rarey, Matthias

2013-01-28

The analysis of small molecule crystal structures is a common way to gather valuable information for drug development. The necessary structural data is usually provided in specific file formats containing only element identities and three-dimensional atomic coordinates as reliable chemical information. Consequently, the automated perception of molecular structures from atomic coordinates has become a standard task in cheminformatics. The molecules generated by such methods must be both chemically valid and reasonable to provide a reliable basis for subsequent calculations. This can be a difficult task since the provided coordinates may deviate from ideal molecular geometries due to experimental uncertainties or low resolution. Additionally, the quality of the input data often differs significantly thus making it difficult to distinguish between actual structural features and mere geometric distortions. We present a method for the generation of molecular structures from atomic coordinates based on the recently published NAOMI model. By making use of this consistent chemical description, our method is able to generate reliable results even with input data of low quality. Molecules from 363 Protein Data Bank (PDB) entries could be perceived with a success rate of 98%, a result which could not be achieved with previously described methods. The robustness of our approach has been assessed by processing all small molecules from the PDB and comparing them to reference structures. The complete data set can be processed in less than 3 min, thus showing that our approach is suitable for large scale applications.

A low-temperature polymorph of m-quinquephenyl.

PubMed

Gomes, Ligia R; Howie, R Alan; Low, John Nicolson; Rodrigues, Ana S M C; Santos, Luís M N B F

2012-12-01

A low-temperature polymorph of 1,1':3',1'':3'',1''':3''',1''''-quinquephenyl (m-quinquephenyl), C(30)H(22), crystallizes in the space group P2(1)/c with two molecules in the asymmetric unit. The crystal is a three-component nonmerohedral twin. A previously reported room-temperature polymorph [Rabideau, Sygula, Dhar & Fronczek (1993). Chem. Commun. pp. 1795-1797] also crystallizes with two molecules in the asymmetric unit in the space group P-1. The unit-cell volume for the low-temperature polymorph is 4120.5 (4) Å(3), almost twice that of the room-temperature polymorph which is 2102.3 (6) Å(3). The molecules in both structures adopt a U-shaped conformation with similar geometric parameters. The structural packing is similar in both compounds, with the molecules lying in layers which stack perpendicular to the longest unit-cell axis. The molecules pack alternately in the layers and in the stacked columns. In both polymorphs, the only interactions between the molecules which can stabilize the packing are very weak C-H...π interactions.

Crystallographic and theoretical studies of an inclusion complex of β-cyclodextrin with fentanyl.

PubMed

Ogawa, Noriko; Nagase, Hiromasa; Loftsson, Thorsteinn; Endo, Tomohiro; Takahashi, Chisato; Kawashima, Yoshiaki; Ueda, Haruhisa; Yamamoto, Hiromitsu

2017-10-15

The crystal structure of an inclusion complex of β-cyclodextrin (β-CD) with fentanyl was determined by single crystal X-ray diffraction analysis. The crystal belongs to the triclinic space group P1 and the complex comprises one fentanyl, two β-CD, and several water molecules. β-CD and fentanyl form a host-guest inclusion complex at a ratio of 2:1 and the asymmetric unit of the complex contains two host molecules (β-CDs) in a head-to-head arrangement that form dimers through hydrogen bonds between the secondary hydroxyl groups of β-CD and one guest molecule. Fentanyl is totally contained within the β-CD cavity and the structure of the phenylethyl part of fentanyl inside the dimeric cavity of the complex is disordered. Furthermore, theoretical molecular conformational calculations were conducted to clarify the mobility of the guest molecule in the β-CD cavity using CONFLEX software. Crystal optimization and crystal energy calculations were also conducted. The results of the theoretical calculations confirmed that the conformation of disorder part 1, which was high in occupancy by crystal structure analysis, was more stable. The phenylethyl part of fentanyl existed in several stable conformations. Copyright © 2017 Elsevier B.V. All rights reserved.

The structure of XIAP BIR2: understanding the selectivity of the BIR domains

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lukacs, Christine, E-mail: cmlukacs230@gmail.com; Belunis, Charles; Crowther, Robert

2013-09-01

The high-resolution crystal structures of apo and peptide-bound XIAP BIR2 are presented and compared with BIR3 structures to understand their selectivity. This crystal system can be used to determine the structures of BIR2–inhibitor complexes. XIAP, a member of the inhibitor of apoptosis family of proteins, is a critical regulator of apoptosis. Inhibition of the BIR domain–caspase interaction is a promising approach towards treating cancer. Previous work has been directed towards inhibiting the BIR3–caspase-9 interaction, which blocks the intrinsic apoptotic pathway; selectively inhibiting the BIR2–caspase-3 interaction would also block the extrinsic pathway. The BIR2 domain of XIAP has successfully been crystallized;more » peptides and small-molecule inhibitors can be soaked into these crystals, which diffract to high resolution. Here, the BIR2 apo crystal structure and the structures of five BIR2–tetrapeptide complexes are described. The structural flexibility observed on comparing these structures, along with a comparison with XIAP BIR3, affords an understanding of the structural elements that drive selectivity between BIR2 and BIR3 and which can be used to design BIR2-selective inhibitors.« less

Kinetic Modeling of Accelerated Stability Testing Enabled by Second Harmonic Generation Microscopy.

PubMed

Song, Zhengtian; Sarkar, Sreya; Vogt, Andrew D; Danzer, Gerald D; Smith, Casey J; Gualtieri, Ellen J; Simpson, Garth J

2018-04-03

The low limits of detection afforded by second harmonic generation (SHG) microscopy coupled with image analysis algorithms enabled quantitative modeling of the temperature-dependent crystallization of active pharmaceutical ingredients (APIs) within amorphous solid dispersions (ASDs). ASDs, in which an API is maintained in an amorphous state within a polymer matrix, are finding increasing use to address solubility limitations of small-molecule APIs. Extensive stability testing is typically performed for ASD characterization, the time frame for which is often dictated by the earliest detectable onset of crystal formation. Here a study of accelerated stability testing on ritonavir, a human immunodeficiency virus (HIV) protease inhibitor, has been conducted. Under the condition for accelerated stability testing at 50 °C/75%RH and 40 °C/75%RH, ritonavir crystallization kinetics from amorphous solid dispersions were monitored by SHG microscopy. SHG microscopy coupled by image analysis yielded limits of detection for ritonavir crystals as low as 10 ppm, which is about 2 orders of magnitude lower than other methods currently available for crystallinity detection in ASDs. The four decade dynamic range of SHG microscopy enabled quantitative modeling with an established (JMAK) kinetic model. From the SHG images, nucleation and crystal growth rates were independently determined.

Assessing the properties of internal standards for quantitative matrix-assisted laser desorption/ionization mass spectrometry of small molecules.

PubMed

Sleno, Lekha; Volmer, Dietrich A

2006-01-01

Growing interest in the ability to conduct quantitative assays for small molecules by matrix-assisted laser desorption/ionization (MALDI) has been the driving force for several recent studies. This present work includes the investigation of internal standards for these analyses using a high-repetition rate MALDI triple quadrupole instrument. Certain physicochemical properties are assessed for predicting possible matches for internal standards for different small molecules. The importance of similar molecular weight of an internal standard to its analyte is seen through experiments with a series of acylcarnitines, having a fixed charge site and growing alkyl chain length. Both acetyl- and hexanoyl-carnitine were systematically assessed with several other acylcarnitine compounds as internal standards. The results clearly demonstrate that closely matched molecular weights between analyte and internal standard are essential for acceptable quantitation results. Using alpha-cyano-4-hydroxycinnamic acid as the organic matrix, the similarities between analyte and internal standard remain the most important parameter and not necessarily their even distribution within the solid sample spot. Several 4-quinolone antibiotics as well as a diverse group of pharmaceutical drugs were tested as internal standards for the 4-quinolone, ciprofloxacin. Quantitative results were shown using the solution-phase properties, log D and pKa, of these molecules. Their distribution coefficients, log D, are demonstrated as a fundamental parameter for similar crystallization patterns of analyte and internal standard. In the end, it was also possible to quantify ciprofloxacin using a drug from a different compound class, namely quinidine, having a similar log D value as the analyte. Copyright 2006 John Wiley & Sons, Ltd.

Selective Encaging of N2O in N2O-N2 Binary Gas Hydrates via Hydrate-Based Gas Separation.

PubMed

Yang, Youjeong; Shin, Donghoon; Choi, Seunghyun; Woo, Yesol; Lee, Jong-Won; Kim, Dongseon; Shin, Hee-Young; Cha, Minjun; Yoon, Ji-Ho

2017-03-21

The crystal structure and guest inclusion behaviors of nitrous oxide-nitrogen (N 2 O-N 2 ) binary gas hydrates formed from N 2 O/N 2 gas mixtures are determined through spectroscopic analysis. Powder X-ray diffraction results indicate that the crystal structure of all the N 2 O-N 2 binary gas hydrates is identified as the structure I (sI) hydrate. Raman spectra for the N 2 O-N 2 binary gas hydrate formed from N 2 O/N 2 (80/20, 60/40, 40/60 mol %) gas mixtures reveal that N 2 O molecules occupy both large and small cages of the sI hydrate. In contrast, there is a single Raman band of N 2 O molecules for the N 2 O-N 2 binary gas hydrate formed from the N 2 O/N 2 (20/80 mol %) gas mixture, indicating that N 2 O molecules are trapped in only large cages of the sI hydrate. From temperature-dependent Raman spectra and the Predictive Soave-Redlich-Kwong (PSRK) model calculation, we confirm the self-preservation of N 2 O-N 2 binary gas hydrates in the temperature range of 210-270 K. Both the experimental measurements and the PSRK model calculations demonstrate the preferential occupation of N 2 O molecules rather than N 2 molecules in the hydrate cages, leading to a possible process for separating N 2 O from gas mixtures via hydrate formation. The phase equilibrium conditions, pseudo-pressure-composition (P-x) diagram, and gas storage capacity of N 2 O-N 2 binary gas hydrates are discussed in detail.

The use of a mini-κ goniometer head in macromolecular crystallography diffraction experiments

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brockhauser, Sandor; UJF–EMBL–CNRS UMI 3265, 6 Rue Jules Horowitz, 38043 Grenoble; Ravelli, Raimond B. G.

2013-07-01

Hardware and software solutions for MX data-collection strategies using the EMBL/ESRF miniaturized multi-axis goniometer head are presented. Most macromolecular crystallography (MX) diffraction experiments at synchrotrons use a single-axis goniometer. This markedly contrasts with small-molecule crystallography, in which the majority of the diffraction data are collected using multi-axis goniometers. A novel miniaturized κ-goniometer head, the MK3, has been developed to allow macromolecular crystals to be aligned. It is available on the majority of the structural biology beamlines at the ESRF, as well as elsewhere. In addition, the Strategy for the Alignment of Crystals (STAC) software package has been developed to facilitatemore » the use of the MK3 and other similar devices. Use of the MK3 and STAC is streamlined by their incorporation into online analysis tools such as EDNA. The current use of STAC and MK3 on the MX beamlines at the ESRF is discussed. It is shown that the alignment of macromolecular crystals can result in improved diffraction data quality compared with data obtained from randomly aligned crystals.« less

Effects of molecular geometry on the properties of compressed diamondoid crystals

DOE PAGES

Yang, Fan; Lin, Yu; Baldini, Maria; ...

2016-11-01

Diamondoids are an intriguing group of carbon-based nanomaterials, which combine desired properties of inorganic nanomaterials and small hydrocarbon molecules with atomic-level uniformity. In this Letter, we report the first comparative study on the effect of pressure on a series of diamondoid crystals with systematically varying molecular geometries and shapes, including zero-dimensional (0D) adamantane; one-dimensional (1D) diamantane, [121]tetramantane, [123]tetramantane, and [1212]pentamantane; two-dimensional (2D) [12312]hexamantane; and three-dimensional (3D) triamantane and [1(2,3)4]pentamantane. We find the bulk moduli of these diamondoid crystals are strongly dependent on the diamondoids’ molecular geometry with 3D [1(2,3)4]pentamantane being the least compressible and 0D adamantane being the most compressible.more » These diamondoid crystals possess excellent structural rigidity and are able to sustain large volume deformation without structural failure even after repetitive pressure loading cycles. These properties are desirable for constructing cushioning devices. Furthermore, we also demonstrate that lower diamondoids outperform the conventional cushioning materials in both the working pressure range and energy absorption density.« less

Crystals and crystallization in oil-in-water emulsions: implications for emulsion-based delivery systems.

PubMed

McClements, David Julian

2012-06-15

Many bioactive components intended for oral ingestion (pharmaceuticals and nutraceuticals) are hydrophobic molecules with low water-solubilities and high melting points, which poses considerable challenges to the formulation of oral delivery systems. Oil-in-water emulsions are often suitable vehicles for the encapsulation and delivery of this type of bioactive component. The bioactive component is usually dissolved in a carrier lipid phase by either dilution and/or heating prior to homogenization, and then the carrier lipid and water phases are homogenized to form an emulsion consisting of small oil droplets dispersed in water. The successful development of this kind of emulsion-based delivery system depends on a good understanding of the influence of crystals on the formation, stability, and properties of emulsions. This review article addresses the physicochemical phenomena associated with the encapsulation, retention, crystallization, release, and absorption of hydrophobic bioactive components within emulsions. This knowledge will be useful for the rational formulation of effective emulsion-based delivery systems for oral delivery of crystalline hydrophobic bioactive components in the food, health care, and pharmaceutical industries. Copyright © 2012 Elsevier B.V. All rights reserved.

Raman spectroscopic investigations on natural samples from the Integrated Ocean Drilling Program (IODP) Expedition 311: indications for heterogeneous compositions in hydrate crystals.

PubMed

Schicks, J M; Ziemann, M A; Lu, H; Ripmeester, J A

2010-12-01

Natural gas hydrates usually are found in the form of structure I, encasing predominantly methane in the hydrate lattices as guest molecules, sometimes also minor amount of higher hydrocarbons, CO2 or H2S. Raman spectroscopy is an approved tool to determine the composition of the hydrate phase. Thus, in this study Raman spectroscopic analyses have been applied to hydrate samples obtained from Integrated Ocean Drilling Program (IODP) Expedition 311 in two different approaches: studying the samples randomly taken from the hydrate core, and--as a new application--mapping small areas on the surface of clear hydrate crystals. The results obtained imply that the gas composition of hydrate, in terms of relative concentrations of CH4 and H2S, is not homogeneous over a core or even within a crystal. The mapping method yielded results with very high lateral resolution, indicating the coexistence of different phases with the same structure but different compositions within a hydrate crystal. Copyright © 2010 Elsevier B.V. All rights reserved.

Approaching Intra- and Interchain Charge Transport of Conjugated Polymers Facilely by Topochemical Polymerized Single Crystals.

PubMed

Yao, Yifan; Dong, Huanli; Liu, Feng; Russell, Thomas P; Hu, Wenping

2017-08-01

Charge transport of small molecules is measured well with scanning tunneling microscopy, conducting atomic force microscopy, break junction, nanopore, and covalently bridging gaps. However, the manipulation and measurement of polymer chains remain a long-standing fundamental issue in conjugated polymers and full of challenge since conjugated polymers are naturally disordered materials. Here, a fundamental breakthrough in generating high-quality conjugated-polymer nanocrystals with extended conjugation and exceptionally high degrees of order using a surface-supported topochemical polymerization method is demonstrated. In the crystal the conjugated-polymer chains are extended along the long axis of the crystal with the side chains perpendicular to the long axis. Devices with conducting channels along the polymer chains show efficient charge transport, nearly two orders of magnitude greater than the interchain charge transport along the π-π stacking direction. This is the first example to clarify intra- and interchain charge transport based on an individual single crystal of conjugated polymers, and demonstrate the importance of intrachain charge transport in plastic electronics. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Modular supramolecular approach for co-crystallization of donors and acceptors into ordered networks

DOEpatents

Stupp, Samuel I.; Stoddart, J. Fraser; Shveyd, Alex K.; Tayi, Alok S.; Sue, Andrew C. H.; Narayanan, Ashwin

2016-09-20

Organic charge-transfer (CT) co-crystals in a mixed stack system are disclosed, wherein a donor molecule (D) and an acceptor molecule (A) occupy alternating positions (DADADA) along the CT axis. A platform is provided which amplifies the molecular recognition of donors and acceptors and produces co-crystals at ambient conditions, wherein the platform comprises (i) a molecular design of the first constituent (.alpha.-complement), (ii) a molecular design of the second compound (.beta.-complement), and (iii) a solvent system that promotes co-crystallization.

Modular supramolecular approach for co-crystallization of donors and acceptors into ordered networks

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stupp, Samuel I.; Stoddart, J. Fraser; Shveyd, Alexander K.

Organic charge-transfer (CT) co-crystals in a mixed stack system are disclosed, wherein a donor molecule (D) and an acceptor molecule (A) occupy alternating positions (DADADA) along the CT axis. A platform is provided which amplifies the molecular recognition of donors and acceptors and produces co-crystals at ambient conditions, wherein the platform comprises (i) a molecular design of the first constituent (.alpha.-complement), (ii) a molecular design of the second compound (.beta.-complement), and (iii) a solvent system that promotes co-crystallization.

Optical Detection and Spectroscopy of Single Molecules in a Solid.

DTIC Science & Technology

1989-03-23

the optical absorption spectrum of single dopant molecules of pentacene in a p-terphenyl host crystal at liquid-helium temperatures. To achieve this...dopant molecules of pentacene in a p-terphenyl host crystal at liquid-helium temperatures. To achieve this, frequency-modulation spectroscopy was combined...solid would provide an important new tool for the study of local absorber-host interactions that would be uncomplicated by the normal averaging over

Use of stabilizing mutations to engineer a charged group within a ligand-binding hydrophobic cavity in T4 lysozyme.

PubMed

Liu, Lijun; Baase, Walter A; Michael, Miya M; Matthews, Brian W

2009-09-22

Both large-to-small and nonpolar-to-polar mutations in the hydrophobic core of T4 lysozyme cause significant loss in stability. By including supplementary stabilizing mutations we constructed a variant that combines the cavity-creating substitution Leu99 --> Ala with the buried charge mutant Met102 --> Glu. Crystal structure determination confirmed that this variant has a large cavity with the side chain of Glu102 located within the cavity wall. The cavity includes a large disk-shaped region plus a bulge. The disk-like region is essentially nonpolar, similar to L99A, while the Glu102 substituent is located in the vicinity of the bulge. Three ordered water molecules bind within this part of the cavity and appear to stabilize the conformation of Glu102. Glu102 has an estimated pKa of about 5.5-6.5, suggesting that it is at least partially charged in the crystal structure. The polar ligands pyridine, phenol and aniline bind within the cavity, and crystal structures of the complexes show one or two water molecules to be retained. Nonpolar ligands of appropriate shape can also bind in the cavity and in some cases exclude all three water molecules. This disrupts the hydrogen-bond network and causes the Glu102 side chain to move away from the ligand by up to 0.8 A where it remains buried in a completely nonpolar environment. Isothermal titration calorimetry revealed that the binding of these compounds stabilizes the protein by 4-6 kcal/mol. For both polar and nonpolar ligands the binding is enthalpically driven. Large negative changes in entropy adversely balance the binding of the polar ligands, whereas entropy has little effect on the nonpolar ligand binding.

Optofluidic sensing from inkjet-printed droplets: the enormous enhancement by evaporation-induced spontaneous flow on photonic crystal biosilica†

PubMed Central

Kong, Xianming; Xi, Yuting; LeDuff, Paul; Li, Erwen; Liu, Ye; Cheng, Li-Jing; Rorrer, Gregory L.; Tan, Hua; Wang, Alan X.

2016-01-01

Novel transducers for detecting an ultra-small volume of an analyte solution play pivotal roles in many applications such as chemical analysis, environmental protection and biomedical diagnosis. Recent advances in optofluidics offer tremendous opportunities for analyzing miniature amounts of samples with high detection sensitivity. In this work, we demonstrate enormous enhancement factors (106–107) of the detection limit for optofluidic analysis from inkjet-printed droplets by evaporation-induced spontaneous flow on photonic crystal biosilica when compared with conventional surface-enhanced Raman scattering (SERS) sensing using the pipette dispensing technology. Our computational fluid dynamics simulation has shown a strong recirculation flow inside the 100 picoliter droplet during the evaporation process due to the thermal Marangoni effect. The combination of the evaporation-induced spontaneous flow in micron-sized droplets and the highly hydrophilic photonic crystal biosilica is capable of providing a strong convection flow to combat the reverse diffusion force, resulting in a higher concentration of the analyte molecules at the diatom surface. In the meanwhile, high density hot-spots provided by the strongly coupled plasmonic nanoparticles with photonic crystal biosilica under a 1.5 μm laser spot are verified by finite-difference time domain simulation, which is crucial for SERS sensing. Using a drop-on-demand inkjet device to dispense multiple 100 picoliter analyte droplets with pinpoint accuracy, we achieved the single molecule detection of Rhodamine 6G and label-free sensing of 4.5 × 10−17 g trinitrotoluene from only 200 nanoliter solution. PMID:27714122

From molecule to solid: The prediction of organic crystal structures

NASA Astrophysics Data System (ADS)

Dzyabchenko, A. V.

2008-10-01

A method for predicting the structure of a molecular crystal based on the systematic search for a global potential energy minimum is considered. The method takes into account unequal occurrences of the structural classes of organic crystals and symmetry of the multidimensional configuration space. The programs of global minimization PMC, comparison of crystal structures CRYCOM, and approximation to the distributions of the electrostatic potentials of molecules FitMEP are presented as tools for numerically solving the problem. Examples of predicted structures substantiated experimentally and the experience of author’s participation in international tests of crystal structure prediction organized by the Cambridge Crystallographic Data Center (Cambridge, UK) are considered.

Detection and recognition of analytes based on their crystallization patterns

DOEpatents

Morozov, Victor [Manassas, VA; Bailey, Charles L [Cross Junction, VA; Vsevolodov, Nikolai N [Kensington, MD; Elliott, Adam [Manassas, VA

2008-05-06

The invention contemplates a method for recognition of proteins and other biological molecules by imaging morphology, size and distribution of crystalline and amorphous dry residues in droplets (further referred to as "crystallization pattern") containing predetermined amount of certain crystal-forming organic compounds (reporters) to which protein to be analyzed is added. It has been shown that changes in the crystallization patterns of a number of amino-acids can be used as a "signature" of a protein added. It was also found that both the character of changer in the crystallization patter and the fact of such changes can be used as recognition elements in analysis of protein molecules.

Electrochemical Quartz Crystal Nanobalance (EQCN) Based Biosensor for Sensitive Detection of Antibiotic Residues in Milk.

PubMed

Bhand, Sunil; Mishra, Geetesh K

2017-01-01

An electrochemical quartz crystal nanobalance (EQCN), which provides real-time analysis of dynamic surface events, is a valuable tool for analyzing biomolecular interactions. EQCN biosensors are based on mass-sensitive measurements that can detect small mass changes caused by chemical binding to small piezoelectric crystals. Among the various biosensors, the piezoelectric biosensor is considered one of the most sensitive analytical techniques, capable of detecting antigens at picogram levels. EQCN is an effective monitoring technique for regulation of the antibiotics below the maximum residual limit (MRL). The analysis of antibiotic residues requires high sensitivity, rapidity, reliability and cost effectiveness. For analytical purposes the general approach is to take advantage of the piezoelectric effect by immobilizing a biosensing layer on top of the piezoelectric crystal. The sensing layer usually comprises a biological material such as an antibody, enzymes, or aptamers having high specificity and selectivity for the target molecule to be detected. The biosensing layer is usually functionalized using surface chemistry modifications. When these bio-functionalized quartz crystals are exposed to a particular substance of interest (e.g., a substrate, inhibitor, antigen or protein), binding interaction occurs. This causes a frequency or mass change that can be used to determine the amount of material interacted or bound. EQCN biosensors can easily be automated by using a flow injection analysis (FIA) setup coupled through automated pumps and injection valves. Such FIA-EQCN biosensors have great potential for the detection of different analytes such as antibiotic residues in various matrices such as water, waste water, and milk.

Purification, crystallization and preliminary crystallographic analysis of a 6-pyruvoyltetrahydropterin synthase homologue from Esherichia coli.

PubMed

Seo, Kyung Hye; Supangat; Kim, Hye Lim; Park, Young Shik; Jeon, Che Ok; Lee, Kon Ho

2008-02-01

6-Pyruvoyltetrahydropterin synthase from E. coli (ePTPS) has been crystallized using the hanging-drop vapour-diffusion method. Hexagonal- and rectangular-shaped crystals were obtained. Diffraction data were collected from the hexagonal and rectangular crystals to 3.0 and 2.3 A resolution, respectively. The hexagonal plate-shaped crystals belonged to space group P321, with unit-cell parameters a = b = 112.59, c = 68.82 A , and contained two molecules in the asymmetric unit. The rectangular crystals belonged to space group I222, with unit-cell parameters a = 112.76, b = 117.66, c = 153.57 A , and contained six molecules in the asymmetric unit. The structure of ePTPS in both crystal forms has been determined by molecular replacement.

Purification, crystallization and preliminary crystallographic analysis of a 6-pyruvoyltetrahydropterin synthase homologue from Esherichia coli

PubMed Central

Seo, Kyung Hye; Supangat; Kim, Hye Lim; Park, Young Shik; Jeon, Che Ok; Lee, Kon Ho

2008-01-01

6-Pyruvoyltetrahydropterin synthase from E. coli (ePTPS) has been crystallized using the hanging-drop vapour-diffusion method. Hexagonal- and rectangular-shaped crystals were obtained. Diffraction data were collected from the hexagonal and rectangular crystals to 3.0 and 2.3 Å resolution, respectively. The hexagonal plate-shaped crystals belonged to space group P321, with unit-cell parameters a = b = 112.59, c = 68.82 Å, and contained two molecules in the asymmetric unit. The rectangular crystals belonged to space group I222, with unit-cell parameters a = 112.76, b = 117.66, c = 153.57 Å, and contained six molecules in the asymmetric unit. The structure of ePTPS in both crystal forms has been determined by molecular replacement. PMID:18271114

Phasing via pure crystallographic least squares: an unexpected feature.

PubMed

Burla, Maria Cristina; Carrozzini, Benedetta; Cascarano, Giovanni Luca; Giacovazzo, Carmelo; Polidori, Giampiero

2018-03-01

Crystallographic least-squares techniques, the main tool for crystal structure refinement of small and medium-size molecules, are for the first time used for ab initio phasing. It is shown that the chief obstacle to such use, the least-squares severe convergence limits, may be overcome by a multi-solution procedure able to progressively recognize and discard model atoms in false positions and to include in the current model new atoms sufficiently close to correct positions. The applications show that the least-squares procedure is able to solve many small structures without the use of important ancillary tools: e.g. no electron-density map is calculated as a support for the least-squares procedure.

Thermal response, catalytic activity, and color change of the first hybrid vanadate containing Bpe guest molecules.

PubMed

Fernández de Luis, Roberto; Urtiaga, M Karmele; Mesa, José L; Larrea, Edurne S; Iglesias, Marta; Rojo, Teófilo; Arriortua, María I

2013-03-04

Four isomorphic compounds with formula [{Co2(H2O)2(Bpe)2}(V4O12)]·4H2O·Bpe, CoBpe 1; [{CoNi(H2O)2(Bpe)2}(V4O12)]·4H2O·Bpe, CoNiBpe 2; [{Co0.6Ni1.4(H2O)2(Bpe)2}(V4O12)]·4H2O·Bpe, NiCoBpe 3; and [{Ni2(H2O)2(Bpe)2}(V4O12)]·4H2O·Bpe, NiBpe 4, have been obtained by hydrothermal synthesis. The crystal structures of CoBpe 1 and NiBpe 4 were determined by single-crystal X-ray diffraction (XRD). The Rietveld refinement of CoNiBpe 2 and NiCoBpe 3 XRD patterns confirms that those are isomorphic. The compounds crystallize in the P1̅ space group, exhibiting a crystal structure constructed from inorganic layers pillared by Bpe ligands. The crystal structure contains intralayer and interlayer channels, in which the crystallization water molecules and Bpe guest molecules, respectively, are located. The solvent molecules establish a hydrogen bonding network with the coordinated water molecules. Thermodiffractometric and thermogravimetric studies showed that the loss of crystallization and coordinated water molecules takes place at different temperatures, giving rise to crystal structure transformations that involve important reduction of the interlayer distance, and strong reduction of crystallinity. The IR, Raman, and UV-vis spectra of the as-synthesized and heated compounds confirm that the structural building blocks and octahedral coordination environment of the metal centers are maintained after the structural transformations. The color change and reversibility of the water molecules uptake/removal were tested showing that the initial color is not completely recovered when the compounds are heated at temperatures higher than 200 °C. The thermal evolution of the magnetic susceptibility indicates one-dimensional antiferromagnetic coupling of the metal centers at high temperatures. For NiCoBpe 3 and NiBpe 4 compounds magnetic ordering is established at low temperatures, as can be judged by the maxima observed in the magnetic susceptibilities. CoNiBpe 2 was proved as catalyst being active for cyanosilylation reactions of aldehydes.

Towards solution and refinement of organic crystal structures by fitting to the atomic pair distribution function.

PubMed

Prill, Dragica; Juhás, Pavol; Billinge, Simon J L; Schmidt, Martin U

2016-01-01

A method towards the solution and refinement of organic crystal structures by fitting to the atomic pair distribution function (PDF) is developed. Approximate lattice parameters and molecular geometry must be given as input. The molecule is generally treated as a rigid body. The positions and orientations of the molecules inside the unit cell are optimized starting from random values. The PDF is obtained from carefully measured X-ray powder diffraction data. The method resembles `real-space' methods for structure solution from powder data, but works with PDF data instead of the diffraction pattern itself. As such it may be used in situations where the organic compounds are not long-range-ordered, are poorly crystalline, or nanocrystalline. The procedure was applied to solve and refine the crystal structures of quinacridone (β phase), naphthalene and allopurinol. In the case of allopurinol it was even possible to successfully solve and refine the structure in P1 with four independent molecules. As an example of a flexible molecule, the crystal structure of paracetamol was refined using restraints for bond lengths, bond angles and selected torsion angles. In all cases, the resulting structures are in excellent agreement with structures from single-crystal data.

Comment on ’Single Pentacene Molecules Detected by Fluorescence Excitation in a P-Terphenyl Crystal’

DTIC Science & Technology

1990-12-10

8217 NO 11 TITLE (include Security Classification) Comment on "Single Pentacene Molecules Detected by Fluorescence Excitation in a p-Terphenyl Crystal" 12...8217 {Continue on reverse it necessary and identify by block numboer) Using h--,Ihly efficient Fluorescence excitation spectroscov of individual pentacene ...molecular impurities in p-terphenvl crystals, we have observed that some pentacene defects exhibit spcntaneous spectral jumps in their resonance frequency at

Relative Sizes of Organic Molecules

NASA Technical Reports Server (NTRS)

2000-01-01

This computer graphic depicts the relative complexity of crystallizing large proteins in order to study their structures through x-ray crystallography. Insulin is a vital protein whose structure has several subtle points that scientists are still trying to determine. Large molecules such as insuline are complex with structures that are comparatively difficult to understand. For comparison, a sugar molecule (which many people have grown as hard crystals in science glass) and a water molecule are shown. These images were produced with the Macmolecule program. Photo credit: NASA/Marshall Space Flight Center (MSFC)

Dynamically controlled crystallization method and apparatus and crystals obtained thereby

NASA Technical Reports Server (NTRS)

Arnowitz, Leonard (Inventor); Steinberg, Emanuel (Inventor)

2003-01-01

A method and apparatus for dynamically controlling the crystallization of molecules including a crystallization chamber (14) or chambers for holding molecules in a precipitant solution, one or more precipitant solution reservoirs (16, 18), communication passages (17, 19) respectively coupling the crystallization chamber(s) with each of the precipitant solution reservoirs, and transfer mechanisms (20, 21, 22, 24, 26, 28) configured to respectively transfer precipitant solution between each of the precipitant solution reservoirs and the crystallization chamber(s). The transfer mechanisms are interlocked to maintain a constant volume of precipitant solution in the crystallization chamber(s). Precipitant solutions of different concentrations are transferred into and out of the crystallization chamber(s) to adjust the concentration of precipitant in the crystallization chamber(s) to achieve precise control of the crystallization process. The method and apparatus can be used effectively to grow crystals under reduced gravity conditions such as microgravity conditions of space, and under conditions of reduced or enhanced effective gravity as induced by a powerful magnetic field.

Continuous diffraction of molecules and disordered molecular crystals

PubMed Central

Yefanov, Oleksandr M.; Ayyer, Kartik; White, Thomas A.; Barty, Anton; Morgan, Andrew; Mariani, Valerio; Oberthuer, Dominik; Pande, Kanupriya

2017-01-01

The intensities of far-field diffraction patterns of orientationally aligned molecules obey Wilson statistics, whether those molecules are in isolation (giving rise to a continuous diffraction pattern) or arranged in a crystal (giving rise to Bragg peaks). Ensembles of molecules in several orientations, but uncorrelated in position, give rise to the incoherent sum of the diffraction from those objects, modifying the statistics in a similar way as crystal twinning modifies the distribution of Bragg intensities. This situation arises in the continuous diffraction of laser-aligned molecules or translationally disordered molecular crystals. This paper develops the analysis of the intensity statistics of such continuous diffraction to obtain parameters such as scaling, beam coherence and the number of contributing independent object orientations. When measured, continuous molecular diffraction is generally weak and accompanied by a background that far exceeds the strength of the signal. Instead of just relying upon the smallest measured intensities or their mean value to guide the subtraction of the background, it is shown how all measured values can be utilized to estimate the background, noise and signal, by employing a modified ‘noisy Wilson’ distribution that explicitly includes the background. Parameters relating to the background and signal quantities can be estimated from the moments of the measured intensities. The analysis method is demonstrated on previously published continuous diffraction data measured from crystals of photosystem II [Ayyer et al. (2016 ▸), Nature, 530, 202–206]. PMID:28808434

A Hierarchical Algorithm for Fast Debye Summation with Applications to Small Angle Scattering

PubMed Central

Gumerov, Nail A.; Berlin, Konstantin; Fushman, David; Duraiswami, Ramani

2012-01-01

Debye summation, which involves the summation of sinc functions of distances between all pair of atoms in three dimensional space, arises in computations performed in crystallography, small/wide angle X-ray scattering (SAXS/WAXS) and small angle neutron scattering (SANS). Direct evaluation of Debye summation has quadratic complexity, which results in computational bottleneck when determining crystal properties, or running structure refinement protocols that involve SAXS or SANS, even for moderately sized molecules. We present a fast approximation algorithm that efficiently computes the summation to any prescribed accuracy ε in linear time. The algorithm is similar to the fast multipole method (FMM), and is based on a hierarchical spatial decomposition of the molecule coupled with local harmonic expansions and translation of these expansions. An even more efficient implementation is possible when the scattering profile is all that is required, as in small angle scattering reconstruction (SAS) of macromolecules. We examine the relationship of the proposed algorithm to existing approximate methods for profile computations, and show that these methods may result in inaccurate profile computations, unless an error bound derived in this paper is used. Our theoretical and computational results show orders of magnitude improvement in computation complexity over existing methods, while maintaining prescribed accuracy. PMID:22707386

Structural Analysis of the Regulatory Domain of ExsA, a Key Transcriptional Regulator of the Type Three Secretion System in Pseudomonas aeruginosa

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shrestha, Manisha; Xiao, Yi; Robinson, Howard

Pseudomonas aeruginosa employs a type three secretion system to facilitate infections in mammalian hosts. The operons encoding genes of structural components of the secretion machinery and associated virulence factors are all under the control of the AraC-type transcriptional activator protein, ExsA. ExsA belongs to a unique subfamily of AraC-proteins that is regulated through protein-protein contacts rather than small molecule ligands. Prior to infection, ExsA is inhibited through a direct interaction with the anti-activator ExsD. To activate ExsA upon host cell contact this interaction is disrupted by the anti-antiactivator protein ExsC. Here we report the crystal structure of the regulatory domainmore » of ExsA, which is known to mediate ExsA dimerization as well as ExsD binding. The crystal structure suggests two models for the ExsA dimer. Both models confirmed the previously shown involvement of helix α-3 in ExsA dimerization but one also suggest a role for helix α-2. These structural data are supported by the observation that a mutation in α-2 greatly diminished the ability of ExsA to activate transcription in vitro. Lastly, additional in vitro transcription studies revealed that a conserved pocket, used by AraC and the related ToxT protein for the binding of small molecule regulators, although present in ExsA is not involved in binding of ExsD.« less

Structural Analysis of the Regulatory Domain of ExsA, a Key Transcriptional Regulator of the Type Three Secretion System in Pseudomonas aeruginosa

DOE PAGES

Shrestha, Manisha; Xiao, Yi; Robinson, Howard; ...

2015-08-28

Pseudomonas aeruginosa employs a type three secretion system to facilitate infections in mammalian hosts. The operons encoding genes of structural components of the secretion machinery and associated virulence factors are all under the control of the AraC-type transcriptional activator protein, ExsA. ExsA belongs to a unique subfamily of AraC-proteins that is regulated through protein-protein contacts rather than small molecule ligands. Prior to infection, ExsA is inhibited through a direct interaction with the anti-activator ExsD. To activate ExsA upon host cell contact this interaction is disrupted by the anti-antiactivator protein ExsC. Here we report the crystal structure of the regulatory domainmore » of ExsA, which is known to mediate ExsA dimerization as well as ExsD binding. The crystal structure suggests two models for the ExsA dimer. Both models confirmed the previously shown involvement of helix α-3 in ExsA dimerization but one also suggest a role for helix α-2. These structural data are supported by the observation that a mutation in α-2 greatly diminished the ability of ExsA to activate transcription in vitro. Lastly, additional in vitro transcription studies revealed that a conserved pocket, used by AraC and the related ToxT protein for the binding of small molecule regulators, although present in ExsA is not involved in binding of ExsD.« less

Structures and anti-inflammatory properties of 4-halogenated -mofebutazones

NASA Astrophysics Data System (ADS)

Reichelt, Hendrik; Paradies, Henrich H.

2018-02-01

The crystal structures of the 4-halogenated (hal: F, Cl, Br)-4-butyl-1-phenyl-1,3-pyrolidine-dione (mofebutazone) are determined, and compared with their solution structures. The racemic 4-halogenated mofebutazone approximants crystallize in a monoclinic space group with four molecules in the unit cell. The 4-hal-mofebutazone molecules reveal strong hydrogen bonding between the hydrogen atom located at the N-2 nitrogen atom and a carbonyl oxygen atom of an adjacent 4-hal-mofebutazone molecule. The hydrogen bond angle for 4-Br-mifebutazone N (2)sbnd H (1)⋯O (1) is 173(3) °, so that the hydrogen bond is essentially linear indicating an infinite chain hydrogen bond network. The 3d and 2d structures are stabilized by π-π and σ-π interactions, short intermolecular distances, and apolar forces between adjacently stacked phenyl rings. Small-angle-X-ray scattering (SAXS) experiments and osmometric measurements reveal the presence of dimers for the 4-hal-mofebutazone molecules. Molecular simulations indicate similar solution structure factors for the 4-hal-mofebutazones solutions, S(Q), and in the solid state. There is a strong indication that the [1,1,0], [1,0,0], and [1,0,0] periodicities of the 4-Brsbnd , 4-Clsbnd and 4-F-mofebutazone in the crystalline solid state were also present in the solution phase. The biochemical and cellular activities of the different 4-hal-mofebutazones were monitored by the magnitude of their inhibition of the PGE2 biosynthesis through the cyclo-oxygenase (COX-1) in macrophages, and on the inhibition of LTD4 (5-lipoxygenase) in polymorphonuclear leukocytes.

Crystal engineering of giant molecules based on perylene diimide conjugated polyhedral oligomeric silsesquioxane nano-atom

NASA Astrophysics Data System (ADS)

Ren, He

Molecular architectures and topologies are found contributing to the formation of supramolecular structures of giant molecules. Dr. Cheng's research group developed a diverse of giant molecules via precisely controlled chemistry synthetic routes. These giant molecules can be categorized into several different families, namely giant surfactants, giant shape amphiphiles and giant polyhedron. By analyzing the hierarchical structures of these carefully designed and precisely synthesized giant molecules, the structural factors which affect, or even dominates, in some cases, the formation of supramolecular structures are revealed in these intensive researches. The results will further contribute to the understanding of dependence of supramolecular structures on molecular designs as well as molecular topology, and providing a practical solution to the scaling up of microscopic molecular functionalities to macroscopic material properties. Molecular Nano Particles (MNPs), including fullerene (C60), POSS, Polyoxometalate (POM) and proteins etc., is defined and applied as a specific type of building blocks in the design and synthesis of giant molecules. The persistence in shape and symmetry is considered as one of the major properties of MNPs. This persistence will support the construction of giant molecules for further supramolecular structures' study by introducing specific shapes, or precisely located side groups which will facilitate self-assembling behaviors with pre-programmed secondary interactions. Dictating material physical properties by its chemical composition is an attractive yet currently failed approach in the study of materials. However, the pursuit of determining material properties by microscopic molecular level properties is never seized, and found its solution when the idea of crystal engineering is raised: should each atom in the material is located exactly where it is designed to be and is properly bonded, the property of the material is hence determined. In such "bottom-up" approach, the precise fabrication of 2 nm 100 nm nanostructures, is of great research interest. In this thesis, crystal engineering of giant molecules based on PDI conjugated POSS Nano-Atom (PDI-BPOSS) nano-atoms via self-assembly is performed and studied. Herein, three different giant molecules were synthesized: shape amphiphile, m-phenyl-(PDI-BPOSS)2 (S1) and tetrahedron, R-(PDI-BPOSS)4 (S2) and S-(PDI-BPOSS)4 (S3). Single crystals were grown for S1 and S2, X-ray diffraction (XRD), Scanning Electron Microscopy (SEM) and transmission electron microscopy (TEM) were performed, and crystal structures of these samples were determined, while hexagonal superlattice without crystal order can be observed for S3 to exhibit crystal-like morphology.

Quantitative single molecule measurements on the interaction forces of poly(L-glutamic acid) with calcite crystals.

PubMed

Sonnenberg, Lars; Luo, Yufei; Schlaad, Helmut; Seitz, Markus; Cölfen, Helmut; Gaub, Hermann E

2007-12-12

The interaction between poly(L-glutamic acid) (PLE) and calcite crystals was studied with AFM-based single molecule force spectroscopy. Block copolymers of poly(ethylene oxide) (PEO) and PLE were synthesized and covalently attached to the tip of an AFM cantilever. In desorption measurements the molecules were allowed to adsorb on the calcite crystal faces and afterward successively desorbed. The corresponding desorption forces were detected with high precision, showing for example a force transition between the two blocks. Because of its importance in the crystallization process in biominerals, the PLE-calcite interaction was investigated as a function of the pH as well as the calcium concentration of the aqueous solution. The sensitivity of the technique was underlined by resolving different interaction forces for calcite (104) and calcite (100).

Synthesis, crystal structure and antioxidant evaluation of C-4-acetamidophenylcalix[4]pyrogallolarene

DOE Office of Scientific and Technical Information (OSTI.GOV)

Abosadiya, Hamza M.; Hasbullah, Siti Aishah; Yamin, Bohari M.

2015-09-25

C-4-acetamidophenylcalix[4]pyrogallolarene was synthesized by an acid catalyzed condensation reaction of pyrogallol with 4-acetamidobenzaldehyde. The compound was characterized by IR, {sup 1}H and {sup 13}C NMR spectroscopy. Single crystal X-ray analysis revealed that the molecule crystallized in a triclinic system with space group Pī and the unit cell dimensions a= 12.2948(16) Å, b= 13.4423(17) Å, c= 13.5906(18) Å, α =107.549(4)°, β =102.034(4)°, γ =90.535(4)°, Z= 1 and V= 2088.2(5) Å{sup 3}. The macrocyclic calix adopts a chair (C{sub 2h}) conformation and the molecule is associated with eight DMSO molecules of crystallization. Antioxidant test by DPPH method showed that the compound exhibitsmore » good antioxidant activity of about 72%.« less

Engineering a light-emitting planar defect within three-dimensional photonic crystals

PubMed Central

Liu, Guiqiang; Chen, Yan; Ye, Zhiqing

2009-01-01

Sandwich structures, constructed from a planar defect of rhodamine-B (RhB)-doped titania (TiO2) and two photonic crystals, were synthesized via the self-assembly method combined with spin-coating. The modification of the spontaneous emission of RhB molecules in such structures was investigated experimentally. The spontaneous emission of RhB-doped TiO2 film with photonic crystals was reduced by a factor of 5.5 over a large bandwidth of 13% of the first-order Bragg diffraction frequency when compared with that of RhB-doped TiO2 film without photonic crystals. The angular dependence of the modification and the photoluminescence lifetime of RhB molecules demonstrate that the strong and wide suppression of the spontaneous emission of the RhB molecules is due to the presence of the photonic band gap. PMID:27877309

Failures of fractional crystallization: ordered co-crystals of isomers and near isomers.

PubMed

Kelley, Steven P; Fábián, László; Brock, Carolyn Pratt

2011-02-01

A list of 270 structures of ordered co-crystals of isomers, near isomers and molecules that are almost the same has been compiled. Searches for structures containing isomers could be automated by the use of IUPAC International Chemical Identifier (InChI™) strings but searches for co-crystals of very similar molecules were more labor intensive. Compounds in which the heteromolecular A···B interactions are clearly better than the average of the homomolecular A···A and B···B interactions were excluded. The two largest structural classes found include co-crystals of configurational diastereomers and of quasienantiomers (or quasiracemates). These two groups overlap. There are 114 co-crystals of diastereomers and the same number of quasiracemates, with 71 structures being counted in both groups; together the groups account for 157 structures or 58% of the total. The large number of quasiracemates is strong evidence for inversion symmetry being very favorable for crystal packing. Co-crystallization of two diastereomers is especially likely if a 1,1 switch of a methyl group and an H atom, or of an inversion of a [2.2.1] or [2.2.2] cage, in one of the diastereomers would make the two molecules enantiomers.

Fv-clasp: An Artificially Designed Small Antibody Fragment with Improved Production Compatibility, Stability, and Crystallizability.

PubMed

Arimori, Takao; Kitago, Yu; Umitsu, Masataka; Fujii, Yuki; Asaki, Ryoko; Tamura-Kawakami, Keiko; Takagi, Junichi

2017-10-03

Antibody fragments are frequently used as a "crystallization chaperone" to aid structural analysis of complex macromolecules that are otherwise crystallization resistant, but conventional fragment formats have not been designed for this particular application. By fusing an anti-parallel coiled-coil structure derived from the SARAH domain of human Mst1 kinase to the variable region of an antibody, we succeeded in creating a novel chimeric antibody fragment of ∼37 kDa, termed "Fv-clasp," which exhibits excellent crystallization compatibility while maintaining the binding ability of the original IgG molecule. The "clasp" and the engineered disulfide bond at the bottom of the Fv suppressed the internal mobility of the fragment and shielded hydrophobic residues, likely contributing to the high heat stability and the crystallizability of the Fv-clasp. Finally, Fv-clasp antibodies showed superior "chaperoning" activity over conventional Fab fragments, and facilitated the structure determination of an ectodomain fragment of integrin α6β1. Copyright © 2017 Elsevier Ltd. All rights reserved.

Tailoring molecular specificity toward a crystal facet: a lesson from biorecognition toward Pt{111}.

PubMed

Ruan, Lingyan; Ramezani-Dakhel, Hadi; Chiu, Chin-Yi; Zhu, Enbo; Li, Yujing; Heinz, Hendrik; Huang, Yu

2013-02-13

Surfactants with preferential adsorption to certain crystal facets have been widely employed to manipulate morphologies of colloidal nanocrystals, while mechanisms regarding the origin of facet selectivity remain an enigma. Similar questions exist in biomimetic syntheses concerning biomolecular recognition to materials and crystal surfaces. Here we present mechanistic studies on the molecular origin of the recognition toward platinum {111} facet. By manipulating the conformations and chemical compositions of a platinum {111} facet specific peptide, phenylalanine is identified as the dominant motif to differentiate {111} from other facets. The discovered recognition motif is extended to convert nonspecific peptides into {111} specific peptides. Further extension of this mechanism allows the rational design of small organic molecules that demonstrate preferential adsorption to the {111} facets of both platinum and rhodium nanocrystals. This work represents an advance in understanding the organic-inorganic interfacial interactions in colloidal systems and paves the way to rational and predictable nanostructure modulations for many applications.

Mosquito larvicide BinAB revealed by de novo phasing with an X-ray laser

PubMed Central

Colletier, Jacques-Philippe; Sawaya, Michael R.; Gingery, Mari; Rodriguez, Jose A.; Cascio, Duilio; Brewster, Aaron S.; Michels-Clark, Tara; Hice, Robert H.; Coquelle, Nicolas; Boutet, Sébastien; Williams, Garth J.; Messerschmidt, Marc; DePonte, Daniel P.; Sierra, Raymond G.; Laksmono, Hartawan; Koglin, Jason E.; Hunter, Mark S.; Park, Hyun-Woo; Uervirojnangkoorn, Monarin; Bideshi, Dennis K.; Brunger, Axel T.; Federici, Brian A.; Sauter, Nicholas K.; Eisenberg, David S.

2016-01-01

Summary BinAB is a naturally occurring paracrystalline larvicide distributed worldwide to combat the devastating diseases borne by mosquitoes. These crystals are composed of homologous molecules, BinA and BinB, which play distinct roles in the multi-step intoxication process, transforming from harmless, robust crystals, to soluble protoxin heterodimers, to internalized mature toxin, and finally toxic oligomeric pores. The small size of the crystals, 50 unit cells per edge, on average, has impeded structural characterization by conventional means. Here, we report the structure of BinAB solved de novo by serial-femtosecond crystallography at an X-ray free-electron laser (XFEL). The structure reveals tyrosine and carboxylate-mediated contacts acting as pH switches to release soluble protoxin in the alkaline larval midgut. An enormous heterodimeric interface appears responsible for anchoring BinA to receptor-bound BinB for co-internalization. Remarkably, this interface is largely composed of propeptides, suggesting that proteolytic maturation would trigger dissociation of the heterodimer and progression to pore formation. PMID:27680699

Interactive and Versatile Navigation of Structural Databases.

PubMed

Korb, Oliver; Kuhn, Bernd; Hert, Jérôme; Taylor, Neil; Cole, Jason; Groom, Colin; Stahl, Martin

2016-05-12

We present CSD-CrossMiner, a novel tool for pharmacophore-based searches in crystal structure databases. Intuitive pharmacophore queries describing, among others, protein-ligand interaction patterns, ligand scaffolds, or protein environments can be built and modified interactively. Matching crystal structures are overlaid onto the query and visualized as soon as they are available, enabling the researcher to quickly modify a hypothesis on the fly. We exemplify the utility of the approach by showing applications relevant to real-world drug discovery projects, including the identification of novel fragments for a specific protein environment or scaffold hopping. The ability to concurrently search protein-ligand binding sites extracted from the Protein Data Bank (PDB) and small organic molecules from the Cambridge Structural Database (CSD) using the same pharmacophore query further emphasizes the flexibility of CSD-CrossMiner. We believe that CSD-CrossMiner closes an important gap in mining structural data and will allow users to extract more value from the growing number of available crystal structures.

The closo-Si{sub 12}C{sub 12} molecule from cluster to crystal: A theoretical prediction

DOE Office of Scientific and Technical Information (OSTI.GOV)

Duan, Xiaofeng F., E-mail: xiaofeng.duan@wpafb.af.mil, E-mail: larry.burggraf@us.af.mil; Air Force Institute of Technology, Wright-Patterson Air Force Base, Ohio 45433; Burggraf, Larry W., E-mail: xiaofeng.duan@wpafb.af.mil, E-mail: larry.burggraf@us.af.mil

2016-03-21

The structure of closo-Si{sub 12}C{sub 12} is unique among stable Si{sub n}C{sub m} isomers (n, m > 4) because of its high symmetry, π–π stacking of C{sub 6} rings and unsaturated silicon atoms at symmetrical peripheral positions. Dimerization potential surfaces reveal various dimerization reactions that form between two closo-Si{sub 12}C{sub 12} molecules through Si–Si bonds at unsaturated Si atoms. As a result the closo-Si{sub 12}C{sub 12} molecule is capable of polymerization to form stable 1D polymer chains, 2D crystal layers, and 3D crystals. 2D crystal structures formed by side-side polymerization satisfy eight Si valences on each monomer without large distortionmore » of the monomer structure. 3D crystals are formed by stacking 2D structures in the Z direction, preserving registry of C{sub 6} rings in monomer moiety.« less

The antitumour drug 7-ethyl-10-hydroxycamptothecin monohydrate and its solid-state hydrolysis mechanism on heating.

PubMed

Ali, Md Ashraf; Noguchi, Shuji; Watanabe, Miteki; Iwao, Yasunori; Itai, Shigeru

2016-10-01

7-Ethyl-10-hydroxycamptothecin [systematic name: (4S)-4,11-diethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione, SN-38] is an antitumour drug which exerts activity through the inhibition of topoisomerase I. The crystal structure of SN-38 as the monohydrate, C 22 H 20 N 2 O 5 ·H 2 O, reveals that it is a monoclinic crystal, with one SN-38 molecule and one water molecule in the asymmetric unit. When the crystal is heated to 473 K, approximately 30% of SN-38 is hydrolyzed at its lactone ring, resulting in the formation of the inactive carboxylate form. The molecular arrangement around the water molecule and the lactone ring of SN-38 in the crystal structure suggests that SN-38 is hydrolyzed by the water molecule at (x, y, z) nucleophilically attacking the carbonyl C atom of the lactone ring at (x - 1, y, z - 1). Hydrogen bonding around the water molecules and the lactone ring appears to promote this hydrolysis reaction: two carbonyl O atoms, which are hydrogen bonded as hydrogen-bond acceptors to the water molecule at (x, y, z), might enhance the nucleophilicity of this water molecule, while the water molecule at (-x, y + 1/2, -z), which is hydrogen bonded as a hydrogen-bond donor to the carbonyl O atom at (x - 1, y, z - 1), might enhance the electrophilicity of the carbonyl C atom.

Thermal oxidation of single crystal aluminum antimonide and materials having the same

DOEpatents

Sherohman, John William; Yee, Jick Hong; Coombs, III, Arthur William; Wu, Kuang Jen J.

2012-12-25

In one embodiment, a method for forming a non-conductive crystalline oxide layer on an AlSb crystal includes heat treating an AlSb crystal in a partial vacuum atmosphere at a temperature conducive for air adsorbed molecules to desorb, surface molecule groups to decompose, and elemental Sb to evaporate from a surface of the AlSb crystal and exposing the AlSb crystal to an atmosphere comprising oxygen to form a crystalline oxide layer on the surface of the AlSb crystal. In another embodiment, a method for forming a non-conductive crystalline oxide layer on an AlSb crystal includes heat treating an AlSb crystal in a non-oxidizing atmosphere at a temperature conducive for decomposition of an amorphous oxidized surface layer and evaporation of elemental Sb from the AlSb crystal surface and forming stable oxides of Al and Sb from residual surface oxygen to form a crystalline oxide layer on the surface of the AlSb crystal.

A first principles prediction of the crystal structure of C6Br2ClFH2

NASA Astrophysics Data System (ADS)

Misquitta, Alston J.; Welch, Gareth W. A.; Stone, Anthony J.; Price, Sarah L.

2008-04-01

We have constructed an intermolecular potential for the 1,3-dibromo-2-chloro-5-fluorobenzene molecule from first principles using SAPT(DFT) interaction energy calculations and the Williams-Stone-Misquitta method for obtaining molecular properties in distributed form. This molecule was included in the fourth Blind Test of crystal structure prediction organised by the Cambridge Crystallographic Data Centre. Using our potential, we have predicted the crystal structure of CBrClFH and found the lowest energy solution to be in excellent agreement with the experimentally observed crystal when it was subsequently revealed.

I. Enabling Single-Chain Surfactants to Form Vesicles by Nonamphiphilic Liquid Crystals in Water II. Controlling Attachment and Ligand-Mediated Adherence of Candida albicans on Monolayers

NASA Astrophysics Data System (ADS)

Varghese, Nisha

This dissertation describes a fundamental study of weak noncovalent interactions and surface forces that exist at the interfaces of various interacting moieties (small molecules or microbes), and its relevance to colloidal and material chemistry. Chapter 1 presents an emulsion system that enables single-chain anionic or nonionic surfactants to sequester and encapsulate certain water-soluble organic salts, leading to the formation of vesicles in water. The water-soluble organic salt in the system comprises of disodium cromoglycate crystals that are emulsified by surfactants in water to form stable liquid crystal droplets. The work provides an exception to the rule of geometric packing factor that dictates formation of micelles by the surfactants in water. Chapter 2 shows that the odd or even number of carbon atoms present in the aliphatic chain of surfactants affect the ability of surfactants to emulsify aqueous-based liquid crystals of disodium cromoglycate. Such an odd-even effect is frequently observed for solid state properties like melting point, heat of fusion and refractive index but is rarely observed for molecules present in solution. When mixed in water, anionic single-chain surfactants with odd number of carbon atoms emulsifies disodium cromoglycate to form liquid crystal droplets, while surfactants with even number of carbon atoms fail to emulsify disodium cromoglycate. Chapter 3 Bolaamphiphiles usually form vesicles only in extreme conditions or in the presence of surfactants. Here, we explore the co-assembly system of synthesized bolaamphiphiles and disodium cromoglycate in water. The combination of the self-assembly forces of the bolaamphiphile and self-associating property of disodium cromoglycate liquid crystals act together at the interface form a unique microemulsion of liquid crystal droplets of disodium cromoglycate embedded in liquid crystal phase. Chapter 4 describes a key event (adhesion) that precedes infections caused by Candida albicans. Adhesion of C. albicans to a surface is a complex process and is governed by nonspecific attachment or multiple ligand-receptor interactions. The work demonstrates that the multiple ligand-receptor interactions used by C. albicans for adherence to a surface can be individually studied using self-assembled monolayers (SAMs) decorated with minimal motif of the ligands. The SAMs were also used to differentiate between the interactions of the two different morphological forms of C. albicans.. Chapter 5 presents a study on small molecules that were used to inhibit biofilm formed by C. albicans. The acyclic triazoles used in the study were not toxic to the C. albicans and were capable of inhibiting biofilm formed by C. albicans. The acyclic triazole can be used as promising candidates to design new antifungal agents. The chapter also reports the synthesis of squarylated homoserine lactones (SHLs) structural mimics of bacterial acyl homoserine lactones (AHLs) to study the inhibitory effects of SHLs on fungal biofilm. The bacterial AHLs are known to repress the growth of C. albicans and control fungal biofilm in native host environment. The synthesized SHLs were non-toxic to C. albicans and failed to inhibit biofilm formed by C. albicans. . Chapter 6 uses gradient nanotopography combined with controlled surface chemistry to confine bacterial biofilm formed by Escherichia coli. The E. coli biofilm were confined within micrometer sized regions of hydrophobic SAMs surrounded by polyol-terminated SAMs. The study reveals that surface with higher topography enhances the ability of the bioinert SAMs to resist bacterial adherence to surface.

Insight of endo-1,4-xylanase II from Trichoderma reesei: conserved water-mediated H-bond and ion pairs interactions.

PubMed

Vijayakumar, Balakrishnan; Velmurugan, Devadasan

2013-12-01

Endo-1,4-Xylanase II is an enzyme which degrades the linear polysaccharide beta-1,4-xylan into xylose. This enzyme shows highest enzyme activity around 55 °C, even without being stabilized by the disulphide bridges. A set of nine high resolution crystal structures of Xylanase II (1.11-1.80 Å) from Trichoderma reesei were selected and analyzed in order to identify the invariant water molecules, ion pairs and water-mediated ionic interactions. The crystal structure (PDB-id: 2DFB) solved at highest resolution (1.11 Å) was chosen as the reference and the remaining structures were treated as mobile molecules. These structures were then superimposed with the reference molecule to observe the invariant water molecules using 3-dimensional structural superposition server. A total of 37 water molecules were identified to be invariant molecules in all the crystal structures, of which 26 invariant molecules have hydrogen bond interactions with the back bone of residues and 21 invariant water molecules have interactions with side chain residues. The structural and functional roles of these water molecules and ion pairs have been discussed. The results show that the invariant water molecules and ion pairs may be involved in maintaining the structural architecture, dynamics and function of the Endo-1,4-Xylanase II.

How the Molecular Packing Affects the Room Temperature Phosphorescence in Pure Organic Compounds: Ingenious Molecular Design, Detailed Crystal Analysis, and Rational Theoretical Calculations.

PubMed

Xie, Yujun; Ge, Yuwei; Peng, Qian; Li, Conggang; Li, Qianqian; Li, Zhen

2017-05-01

Long-lived phosphorescence at room temperature (RTP) from pure organic molecules is rare. Recent research reveals various crystalline organic molecules can realize RTP with lifetimes extending to the magnitude of second. There is little research on how molecular packing affecting RTP. Three compounds are designed with similar optical properties in solution, but tremendously different solid emission characteristics. By investigating the molecular packing arrangement in single crystals, it is found that the packing style of the compact face to face favors of long phosphorescence lifetime and high photoluminescence efficiency, with the lifetime up to 748 ms observed in the crystal of CPM ((9H-carbazol-9-yl)(phenyl)methanone). Theoretical calculation analysis also reveals this kind of packing style can remarkably reduce the singlet excited energy level and prompt electron communication between dimers. Surprisingly, CPM has two very similar single crystals, labeled as CPM and CPM-A, with almost identical crystal data, and the only difference is that molecules in CPM-A crystal take a little looser packing arrangement. X-ray diffraction and cross-polarization under magic spinning 13 C NMR spectra double confirm that they are different crystals. Interestingly, CPM-A crystal shows negligible RTP compared to the CPM crystal, once again proving that the packing style is critical to the RTP property. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sliwiak, Joanna; Dauter, Zbigniew; Kowiel, Marcin

Hyp-1, a pathogenesis-related class 10 (PR-10) protein from St John's wort ( Hypericum perforatum), was crystallized in complex with the fluorescent probe 8-anilino-1-naphthalene sulfonate (ANS). The highly pseudosymmetric crystal has 28 unique protein molecules arranged in columns with sevenfold translational noncrystallographic symmetry (tNCS) along c and modulated X-ray diffraction with intensity crests at l = 7 n and l = 7 n ± 3. The translational NCS is combined with pseudotetragonal rotational NCS. The crystal was a perfect tetartohedral twin, although detection of twinning was severely hindered by the pseudosymmetry. The structure determined at 2.4 Å resolution reveals that themore » Hyp-1 molecules (packed as β-sheet dimers) have three novel ligand-binding sites (two internal and one in a surface pocket), which was confirmed by solution studies. In addition to 60 Hyp-1-docked ligands, there are 29 interstitial ANS molecules distributed in a pattern that violates the arrangement of the protein molecules and is likely to be the generator of the structural modulation. In particular, whenever the stacked Hyp-1 molecules are found closer together there is an ANS molecule bridging them.« less

Oxygen transport as a structure probe for heterogeneous polymeric systems

NASA Astrophysics Data System (ADS)

Hu, Yushan

Although permeability of small molecules is often measured as an important performance property, deeper analysis of the transport characteristics provides insight into polymer structure, especially if used in combination with other characterization techniques. Transport of small gas molecules senses the permeable amorphous structure and probes the nature of free volume. This work focuses on oxygen transport, supplemented with other methods of physical analysis, as a probe for: (1) the nature of free volume and crystalline morphology in the crystallized glassy state, (2) the nature of free volume and hierarchical structure in liquid crystalline polymers, and (3) the role of dispersed polyamide phase geometry on oxygen barrier properties of poly(ethylene terephthalate) (PET)/polyamide blends. In the first part, the improvement in oxygen-barrier properties of glassy polyesters by crystallization was examined. Examples included poly(ethylene naphthalate) (PEN), and a copolymer based on PET in which 55 mol% terephthalate was replaced with 4,4'-bibenzoate. Explanation of the unexpectedly high solubility of crystallized PEN required a two-phase transport model consisting of an impermeable crystalline phase of constant density and a permeable amorphous phase of variable density. The resulting relationship between oxygen solubility and amorphous phase density was consistent with free volume concepts of gas sorption. In the second part, oxygen barrier properties of liquid crystalline (LC) polyesters based on poly(diethylene glycol 4,4'-bibenzoate) (PDEGBB) were studied. This study extended the 2-phase transport model for oxygen transport of non-LC crystalline polymers to a smectic LCP. It was possible to systematically vary the solid state structure of (PDEGBB) from LC glass to crystallized LC glass. The results were consistent with a liquid crystalline state intermediate between the permeable amorphous glass and the impermeable 3-dimensional crystal. In this interpretation, LC order naturally led to inherently low gas solubility. In the third part, improvement of gas-barrier properties of poly(ethylene terephthalate) (PET) by blending with an aromatic polyamide, either poly(m-xylylene adipamide) (MXD6) or a copolyamide based on MXD6 in which 12 mol% adipamide was replaced with isophthalamide (MXD6-12I), was studied. Aromatic polyamides provided higher barrier than aliphatic polyamides, and unlike aliphatic polyamides, the aromatic polyamides retained high barrier under conditions of high humidity, making them more suitable for beverage packaging applications. (Abstract shortened by UMI.)

Protein Innovations Advance Drug Treatments, Skin Care

NASA Technical Reports Server (NTRS)

2012-01-01

Dan Carter carefully layered the sheets of tracing paper on the light box. On each sheet were renderings of the atomic components of an essential human protein, one whose structure had long been a mystery. With each layer Carter laid down, a never-before-seen image became clearer. Carter joined NASA s Marshall Space Flight Center in 1985 and began exploring processes of protein crystal growth in space. By bouncing intense X-rays off the crystals, researchers can determine the electron densities around the thousands of atoms forming the protein molecules, unveiling their atomic structures. Cultivating crystals of sufficient quality on Earth was problematic; the microgravity conditions of space were far more accommodating. At the time, only a few hundred protein structures had been mapped, and the methods were time consuming and tedious. Carter hoped his work would help reveal the structure of human serum albumin, a major protein in the human circulatory system responsible for ferrying numerous small molecules in the blood. More was at stake than scientific curiosity. Albumin has a high affinity for most of the world s pharmaceuticals, Carter explains, and its interaction with drugs can change their safety and efficacy. When a medication enters the bloodstream a cancer chemotherapy drug, for example a majority of it can bind with albumin, leaving only a small percentage active for treatment. How a drug interacts with albumin can influence considerations like the necessary effective dosage, playing a significant role in the design and application of therapeutic measures. In spite of numerous difficulties, including having no access to microgravity following the 1986 Space Shuttle Challenger disaster, the image Carter had hoped to see was finally clarifying. In 1988, his lab had acquired specialized X-ray and detection equipment a tipping point. Carter and his colleagues began to piece together albumin s portrait, the formation of its electron densities coalescing on the sheets of tracing paper he arranged on the light box. While space-grown crystals were ultimately not involved in the achievement, a year later, Carter says, we were on the cover of Science magazine, having determined the atomic structure of albumin.

Computed crystal energy landscapes for understanding and predicting organic crystal structures and polymorphism.

PubMed

Price, Sarah Sally L

2009-01-20

The phenomenon of polymorphism, the ability of a molecule to adopt more than one crystal structure, is a well-established property of crystalline solids. The possible variations in physical properties between polymorphs make the reliable reproduction of a crystalline form essential for all research using organic materials, as well as quality control in manufacture. Thus, the last two decades have seen both an increase in interest in polymorphism and the availability of the computer power needed to make the computational prediction of organic crystal structures a practical possibility. In the past decade, researchers have made considerable improvements in the theoretical basis for calculating the sets of structures that are within the energy range of possible polymorphism, called crystal energy landscapes. It is common to find that a molecule has a wide variety of ways of packing with lattice energy within a few kilojoules per mole of the most stable structure. However, as we develop methods to search for and characterize "all" solid forms, it is also now usual for polymorphs and solvates to be found. Thus, the computed crystal energy landscape reflects and to an increasing extent "predicts" the emerging complexity of the solid state observed for many organic molecules. This Account will discuss the ways in which the calculation of the crystal energy landscape of a molecule can be used as a complementary technique to solid form screening for polymorphs. Current methods can predict the known crystal structure, even under "blind test" conditions, but such successes are generally restricted to those structures that are the most stable over a wide range of thermodynamic conditions. The other low-energy structures can be alternative polymorphs, which have sometimes been found in later experimental studies. Examining the computed structures reveals the various compromises between close packing, hydrogen bonding, and pi-pi stacking that can result in energetically feasible structures. Indeed, we have observed that systems with many almost equi-energetic structures that contain a common interchangeable motif correlate with a tendency to disorder and problems with control of the crystallization product. Thus, contrasting the computed crystal energy landscape with the known crystal structures of a given molecule provides a valuable complement to solid form screening, and the examination of the low-energy structures often leads to a rationalization of the forms found.

Design and Synthesis of Novel Discotic Liquid Crystals

NASA Astrophysics Data System (ADS)

Kayal, Himadri Sekhar

Columnar mesophases of discotic liquid crystals (DLCs) have attracted much attention as organic semiconductors and have been tested as active materials in light-emitting diodes, photovoltaic solar cells, and field-effect transistors. However, devices based on DLCs have shown lower performance than devices based on polymeric and small molecule glass semiconductors, despite their superior charge conducting and advantages self-organizing properties. Most DLCs also require relatively complex processing conditions for the preparation of electronic devices, which is another significant disadvantage. Consequently, new types of DLCs are sought-after to overcome these limitations and described in this thesis are new types of discotic materials and their synthesis. Chapters 2 and 3 describe star-shaped discotic molecules for donor-acceptor columnar structures and as novel flexible core discotic molecules. Presented are the first examples of star-shaped heptamers of donor and acceptor discotic molecules which have six hexaalkoxy triphenylene ligands and a hexaazatriphenylene hexacarboxylate core or a hexaazatriphenylene hexaamide core. The hexaazatriphenylene cores were chosen because of their electron deficient character while the hexaalkoxy triphenylenes are known to be electron rich. Envisioned is the formation of super-columns in which the heptamers stack on top of each other and generate a material with electron acceptor and electron donor channels separated by aliphatic chains. This is an important difference to previously reported donor-acceptor star-shaped structures that were connected via conjugated linkers and do not form separate columnar stacks. Star-shaped DLCs based on small aromatic groups linked together by short flexible spacers may represent a novel type of discotic core structure that does not require peripheral flexible chains. Softening of the core by the spacer group is expected to sufficiently lower melting points and not interfere with the columnar stacking as long as a disc-shaped structure can be adopted. Presented here are synthetic approaches towards novel hexa(thiophen-2-yl)alkyl)benzene derivatives as star-shaped hetero-heptamer discotic cores. New ionic and polymerizable discotic liquid crystals based on the commercial dye tetraazaporphyrin are presented in Chapters 4 and 5. Both areas have been given little attention despite their importance for the preparation of stable films for devices. Tetraazaporphyrins containing azide and acetylene groups at the end of aliphatic spacers have been prepared and cross-linked by cycloaddition (click chemistry). Some derivatives form columnar mesophases and could be thermally cross-linked in their columnar mesophase and their copper catalyzed cross-linking in Langmuir and Langmuir-Blodgett layers was also successful.

Crystal structure of benzyl (E)-2-(3,4-di-meth-oxy-benzyl-idene)hydrazine-1-carbodi-thio-ate.

PubMed

Tan, Yew-Fung; Break, Mohammed Khaled Bin; Tahir, M Ibrahim M; Khoo, Teng-Jin

2015-02-01

The title compound, C17H18N2O2S2, synthesized via a condensation reaction between S-benzyl di-thio-carbazate and 3,4-di-meth-oxy-benzaldehyde, crystallized with two independent mol-ecules (A and B) in the asymmetric unit. Both mol-ecules have an L-shape but differ in the orientation of the benzyl ring with respect to the 3,4-di-meth-oxy-benzyl-idine ring, this dihedral angle is 65.59 (8)° in mol-ecule A and 73.10 (8)° in mol-ecule B. In the crystal, the A and B mol-ecules are linked via pairs of N-H⋯S hydrogen bonds, forming dimers with an R 2 (2)(8) ring motif. The dimers are linked via pairs of C-H⋯O hydrogen bonds, giving inversion dimers of dimers. These units are linked by C-H⋯π inter-actions, forming ribbons propagating in the [100] direction.

Phase properties of elastic waves in systems constituted of adsorbed diatomic molecules on the (001) surface of a simple cubic crystal

NASA Astrophysics Data System (ADS)

Deymier, P. A.; Runge, K.

2018-03-01

A Green's function-based numerical method is developed to calculate the phase of scattered elastic waves in a harmonic model of diatomic molecules adsorbed on the (001) surface of a simple cubic crystal. The phase properties of scattered waves depend on the configuration of the molecules. The configurations of adsorbed molecules on the crystal surface such as parallel chain-like arrays coupled via kinks are used to demonstrate not only linear but also non-linear dependency of the phase on the number of kinks along the chains. Non-linear behavior arises for scattered waves with frequencies in the vicinity of a diatomic molecule resonance. In the non-linear regime, the variation in phase with the number of kinks is formulated mathematically as unitary matrix operations leading to an analogy between phase-based elastic unitary operations and quantum gates. The advantage of elastic based unitary operations is that they are easily realizable physically and measurable.

X-ray transparent Microfluidics for Protein Crystallization and Biomineralization

NASA Astrophysics Data System (ADS)

Opathalage, Achini

Protein crystallization demands the fundamental understanding of nucleation and applying techniques to find the optimal conditions to achieve the kinetic pathway for a large and defect free crystal. Classical nucleation theory predicts that the nucleation occurs at high supersaturation conditions. In this dissertation we sought out to develop techniques to attain optimal supersaturation profile to a large defect free crystal and subject it to in-situ X-ray diffraction using microfluidics. We have developed an emulsion-based serial crystallographic technology in nanolitre-sized droplets of protein solution encapsulated in to nucleate one crystal per drop. Diffraction data are measured, one crystal at a time, from a series of room temperature crystals stored on an X-ray semi-transparent microfluidic chip, and a 93% complete data set is obtained by merging single diffraction frames taken from different un-oriented crystals. As proof of concept, the structure of Glucose Isomerase was solved to 2.1 A. We have developed a suite of X-ray semi-transparent micrfluidic devices which enables; controlled evaporation as a method of increasing supersaturation and manipulating the phase space of proteins and small molecules. We exploited the inherently high water permeability of the thin X-ray semi-transparent devices as a mean of increasing the supersaturation by controlling the evaporation. We fabricated the X-ray semi-transparent version of the PhaseChip with a thin PDMS membrane by which the storage and the reservoir layers are separated, and studies the phase transition of amorphous CaCO3.

Structural insights into eRF3 and stop codon recognition by eRF1

PubMed Central

Cheng, Zhihong; Saito, Kazuki; Pisarev, Andrey V.; Wada, Miki; Pisareva, Vera P.; Pestova, Tatyana V.; Gajda, Michal; Round, Adam; Kong, Chunguang; Lim, Mengkiat; Nakamura, Yoshikazu; Svergun, Dmitri I.; Ito, Koichi; Song, Haiwei

2009-01-01

Eukaryotic translation termination is mediated by two interacting release factors, eRF1 and eRF3, which act cooperatively to ensure efficient stop codon recognition and fast polypeptide release. The crystal structures of human and Schizosaccharomyces pombe full-length eRF1 in complex with eRF3 lacking the GTPase domain revealed details of the interaction between these two factors and marked conformational changes in eRF1 that occur upon binding to eRF3, leading eRF1 to resemble a tRNA molecule. Small-angle X-ray scattering analysis of the eRF1/eRF3/GTP complex suggested that eRF1's M domain contacts eRF3's GTPase domain. Consistently, mutation of Arg192, which is predicted to come in close contact with the switch regions of eRF3, revealed its important role for eRF1's stimulatory effect on eRF3's GTPase activity. An ATP molecule used as a crystallization additive was bound in eRF1's putative decoding area. Mutational analysis of the ATP-binding site shed light on the mechanism of stop codon recognition by eRF1. PMID:19417105

Highly Viscous States Affect the Browning of Atmospheric Organic Particulate Matter

PubMed Central

2018-01-01

Initially transparent organic particulate matter (PM) can become shades of light-absorbing brown via atmospheric particle-phase chemical reactions. The production of nitrogen-containing compounds is one important pathway for browning. Semisolid or solid physical states of organic PM might, however, have sufficiently slow diffusion of reactant molecules to inhibit browning reactions. Herein, organic PM of secondary organic material (SOM) derived from toluene, a common SOM precursor in anthropogenically affected environments, was exposed to ammonia at different values of relative humidity (RH). The production of light-absorbing organonitrogen imines from ammonia exposure, detected by mass spectrometry and ultraviolet–visible spectrophotometry, was kinetically inhibited for RH < 20% for exposure times of 6 min to 24 h. By comparison, from 20% to 60% RH organonitrogen production took place, implying ammonia uptake and reaction. Correspondingly, the absorption index k across 280 to 320 nm increased from 0.012 to 0.02, indicative of PM browning. The k value across 380 to 420 nm increased from 0.001 to 0.004. The observed RH-dependent behavior of ammonia uptake and browning was well captured by a model that considered the diffusivities of both the large organic molecules that made up the PM and the small reactant molecules taken up from the gas phase into the PM. Within the model, large-molecule diffusivity was calculated based on observed SOM viscosity and evaporation. Small-molecule diffusivity was represented by the water diffusivity measured by a quartz-crystal microbalance. The model showed that the browning reaction rates at RH < 60% could be controlled by the low diffusivity of the large organic molecules from the interior region of the particle to the reactive surface region. The results of this study have implications for accurate modeling of atmospheric brown carbon production and associated influences on energy balance. PMID:29532020

Highly Viscous States Affect the Browning of Atmospheric Organic Particulate Matter.

PubMed

Liu, Pengfei; Li, Yong Jie; Wang, Yan; Bateman, Adam P; Zhang, Yue; Gong, Zhaoheng; Bertram, Allan K; Martin, Scot T

2018-02-28

Initially transparent organic particulate matter (PM) can become shades of light-absorbing brown via atmospheric particle-phase chemical reactions. The production of nitrogen-containing compounds is one important pathway for browning. Semisolid or solid physical states of organic PM might, however, have sufficiently slow diffusion of reactant molecules to inhibit browning reactions. Herein, organic PM of secondary organic material (SOM) derived from toluene, a common SOM precursor in anthropogenically affected environments, was exposed to ammonia at different values of relative humidity (RH). The production of light-absorbing organonitrogen imines from ammonia exposure, detected by mass spectrometry and ultraviolet-visible spectrophotometry, was kinetically inhibited for RH < 20% for exposure times of 6 min to 24 h. By comparison, from 20% to 60% RH organonitrogen production took place, implying ammonia uptake and reaction. Correspondingly, the absorption index k across 280 to 320 nm increased from 0.012 to 0.02, indicative of PM browning. The k value across 380 to 420 nm increased from 0.001 to 0.004. The observed RH-dependent behavior of ammonia uptake and browning was well captured by a model that considered the diffusivities of both the large organic molecules that made up the PM and the small reactant molecules taken up from the gas phase into the PM. Within the model, large-molecule diffusivity was calculated based on observed SOM viscosity and evaporation. Small-molecule diffusivity was represented by the water diffusivity measured by a quartz-crystal microbalance. The model showed that the browning reaction rates at RH < 60% could be controlled by the low diffusivity of the large organic molecules from the interior region of the particle to the reactive surface region. The results of this study have implications for accurate modeling of atmospheric brown carbon production and associated influences on energy balance.

Microfluidic Devices for Studying Biomolecular Interactions

NASA Technical Reports Server (NTRS)

Wilson, Wilbur W.; Garcia, Carlos d.; Henry, Charles S.

2006-01-01

Microfluidic devices for monitoring biomolecular interactions have been invented. These devices are basically highly miniaturized liquid-chromatography columns. They are intended to be prototypes of miniature analytical devices of the laboratory on a chip type that could be fabricated rapidly and inexpensively and that, because of their small sizes, would yield analytical results from very small amounts of expensive analytes (typically, proteins). Other advantages to be gained by this scaling down of liquid-chromatography columns may include increases in resolution and speed, decreases in the consumption of reagents, and the possibility of performing multiple simultaneous and highly integrated analyses by use of multiple devices of this type, each possibly containing multiple parallel analytical microchannels. The principle of operation is the same as that of a macroscopic liquid-chromatography column: The column is a channel packed with particles, upon which are immobilized molecules of the protein of interest (or one of the proteins of interest if there are more than one). Starting at a known time, a solution or suspension containing molecules of the protein or other substance of interest is pumped into the channel at its inlet. The liquid emerging from the outlet of the channel is monitored to detect the molecules of the dissolved or suspended substance(s). The time that it takes these molecules to flow from the inlet to the outlet is a measure of the degree of interaction between the immobilized and the dissolved or suspended molecules. Depending on the precise natures of the molecules, this measure can be used for diverse purposes: examples include screening for solution conditions that favor crystallization of proteins, screening for interactions between drugs and proteins, and determining the functions of biomolecules.

Fluid Physics and Macromolecular Crystal Growth in Microgravity

NASA Technical Reports Server (NTRS)

Helliwell, John R.; Snell, Edward H.; Chayen, Naomi E.; Judge, Russell A.; Boggon, Titus J.; Pusey, M. L.; Rose, M. Franklin (Technical Monitor)

2000-01-01

The first protein crystallization experiment in microgravity was launched in April, 1981 and used Germany's Technologische Experimente unter Schwerelosigkeit (TEXUS 3) sounding rocket. The protein P-galactosidase (molecular weight 465Kda) was chosen as the sample with a liquid-liquid diffusion growth method. A sliding device brought the protein, buffer and salt solution into contact when microgravity was reached. The sounding rocket gave six minutes of microgravity time with a cine camera and schlieren optics used to monitor the experiment, a single growth cell. In microgravity a strictly laminar diffusion process was observed in contrast to the turbulent convection seen on the ground. Several single crystals, approx 100micron in length, were formed in the flight which were of inferior but of comparable visual quality to those grown on the ground over several days. A second experiment using the same protocol but with solutions cooled to -8C (kept liquid with glycerol antifreeze) again showed laminar diffusion. The science of macromolecular structural crystallography involves crystallization of the macromolecule followed by use of the crystal for X-ray diffraction experiments to determine the three dimensional structure of the macromolecule. Neutron protein crystallography is employed for elucidation of H/D exchange and for improved definition of the bound solvent (D20). The structural information enables an understanding of how the molecule functions with important potential for rational drug design, improved efficiency of industrial enzymes and agricultural chemical development. The removal of turbulent convection and sedimentation in microgravity, and the assumption that higher quality crystals will be produced, has given rise to the growing number of crystallization experiments now flown. Many experiments can be flown in a small volume with simple, largely automated, equipment - an ideal combination for a microgravity experiment. The term "protein crystal growth" is often historically used to describe these microgravity experiments. This is somewhat inaccurate as the field involves the study of many varied biological molecules including viruses, proteins, DNA, RNA and complexes of those structures. For this reason we use the term macromolecular crystal growth. In this chapter we review a series of diagnostic microgravity crystal growth experiments carried out principally using the European Space Agency (ESA) Advanced Protein Crystallization Facility (APCF). We also review related research, both experimental and theoretical, on the aspects of microgravity fluid physics that affect microgravity protein crystal growth. Our experiments have revealed some surprises that were not initially expected. We discuss them here in the context of practical lessons learnt and how to maximize the limited microgravity opportunities available.

Crystal structure of bis-(N-methyl-N-phenyl-amino)-tris-ulfane.

PubMed

Barany, George; Henley, Matthew J; Polski, Lauren A; Schroll, Alayne L; Young, Victor G

2015-07-01

The title compound, C14H16N2S3, crystallized with two independent mol-ecules [(1 a ) and (1 b )] in the asymmetric unit. Both mol-ecules display a pseudo-trans conformation. The two consecutive S-S bond lengths of the tris-ulfane unit of mol-ecule (1 a ) are 2.06 (3) and 2.08 (3) Å, and 2.08 (3) and 2.07 (2) Å for mol-ecule (1 b ). Torsion angles about each of the two S-S bonds are 86.6 (2) and 87.0 (2)° for (1 a ), and -84.6 (2) and -85.9 (2)° for (1 b ). The core atoms, viz. the N-S-S-S-N moiety, of the two mol-ecules superimpose well if one is inverted on the other, but the phenyl groups do not. Thus, the two units are essentially conformational enanti-omers. In mol-ecule (1 a ), the two phenyl rings are inclined to one another by 86.7 (3)°, and in mol-ecule (1 b ), by 81.1 (3)°. In the crystal, mol-ecules are linked via C-H⋯π inter-actions, forming sheets lying parallel to (010).

Fe3O4-in-silica super crystal of defined interstices for single protein molecules entrapment under magnetic flux.

PubMed

Ye, Lin; Yu, Chih Hao; Jiang, PengJu; Qiu, Lin; Ng, Olivia T W; Yung, Ken K L; He, Heyong; Tsang, Shik Chi

2010-09-28

Confocal fluorescence demonstrates that single molecules of dye-labelled Cytochrome C or B5 containing paramagnetic Fe(III) can be magnetically placed into the interstices of super-crystal which is composed of three dimensional regular arrays of Fe(3)O(4) nanoparticles.

A Study of Biomolecules as Growth Modifiers of Calcium Oxalate Crystals

NASA Astrophysics Data System (ADS)

Kwak, Junha John

Crystallization processes are ubiquitous in nature, science, and technology. Controlling crystal growth is pivotal in many industries as material properties and functions can be tailored by tuning crystal habits (e.g. size, shape, phase). In biomineralization, organisms exert excellent control over bottom-up synthesis and assembly of inorganic-organic structures (e.g. bones, teeth, exoskeletons). This is made possible by growth modifiers that range from small molecules to macromolecules, such as proteins. Molecular recognition of the mineral phase allows proteins to function as nucleation templates, matrices, and growth inhibitors or promoters. We are interested in taking a biomimetic approach to control crystallization via biomolecular growth modifiers. We investigated calcium oxalate monohydrate (COM), found in plants and kidney stones, as a model system of crystallization. We studied the effects of four common proteins on COM crystallization: bovine serum albumin (BSA), transferrin, lactoferrin, and lysozyme. Through kinetic studies of COM crystallization, we classified BSA and lysozyme as COM growth inhibitor and promoter respectively. Their inhibition and promotion effects were also evident in the macroscopic crystal habit. Through adsorption and microscopy experiments, we showed that BSA exhibits binding specificity for the apical surfaces of macroscopic COM crystals. Lysozyme, on the other, functions via a non-binding mechanism at the surface to accelerate the growth of the apical surfaces. We also synthesized and studied peptides derived from the protein primary sequences to identify putative domains responsible for these inhibition and promotion effects. Collectively, our study of physiologically relevant biomolecules suggests potential roles of COM modifiers in pathological crystallization and helps to develop guidelines for rational design of biomolecular growth modifiers for applications in crystal engineering.

Synthesis and crystal structure of the coordination compound of pyridoxine with manganese sulfate

DOE Office of Scientific and Technical Information (OSTI.GOV)

Furmanova, N. G., E-mail: furm@ns.crys.ras.ru; Verin, I. A.; Shyityeva, N.

2011-11-15

The reaction of pyridoxine with manganese sulfate in an aqueous solution gave the coordination compound MnSO{sub 4} {center_dot} 2C{sub 8}H{sub 11}O{sub 3}N {center_dot} 2H{sub 2}O (I). The structure of I was determined from single-crystal X-ray diffraction data. In the centrosymmetric complex (sp. gr. P1-bar, Z = 1), the Mn atom is coordinated by two pyridoxine molecules and two water molecules, thus adopting an octahedral coordination. The sulfate anion is also at a center of symmetry and, consequently, is disordered. The pyridoxine molecules are coordinated to the metal atom through the oxygen atoms of the deprotonated hydroxyl group and the CH{submore » 2}OH group that retains the hydrogen atom. The nitrogen atom is protonated in such a way that the heterocycle assumes a pyridinium character. The crystal structure also contains six water molecules of crystallization. A thermogravimetric study showed that the decomposition of I occurs in several successive steps, such as dehydration, the combustion of organic ligands, and the formation of an inorganic residue.« less

Amphiphilic inclusion spaces for various guests and regulation of fluorescence intensity of 1,8-bis(4-aminophenyl)anthracene crystals.

PubMed

Sugino, Misa; Hatanaka, Keisuke; Araki, Yusuke; Hisaki, Ichiro; Miyata, Mikiji; Tohnai, Norimitsu

2014-03-10

A host framework for inclusion of various guest molecules was investigated by preparation of inclusion crystals of 1,8-bis(4-aminophenyl)anthracene (1,8-BAPA) with organic solvents. X-ray crystallographic analysis revealed construction of the same inclusion space incorporating 1,8-BAPA and eight guest molecules including both non-polar (benzene) and polar guests (N,N-dimethylformamide, DMF). Fluorescence efficiencies varied depending on guest molecule polarity; DMF inclusion crystals exhibited the highest fluorescence intensity (ΦF=0.40), four times as high as that of a benzene inclusion crystal (ΦF=0.10). According to systematic investigations of inclusion phenomena, strong host–guest interactions and filling of the inclusion space led to a high fluorescence intensity. Temperature-dependent fluorescence spectral measurements revealed these factors effectively immobilised the host framework. Although hydrogen bonding commonly decreases fluorescence intensity, the present study demonstrated that such strong interactions provide excellent conditions for fluorescence enhancement. Thus, this remarkable behaviour has potential application toward sensing of highly polar molecules, such as biogenic compounds.

Synthesis and Crystal Structure of a Chalcone Derivative

NASA Astrophysics Data System (ADS)

Singh, Vikram D.; Salian, Vinutha V.; Narayana, B.; Sarojini, B. K.; Kamni; Anthal, Sumati; Kant, Rajni

2017-12-01

(2E)-3-(anthrance-9-yl)-1-(3,4-dichlorophenyl)prop-2-en-1-one [C23H14OCl2] is synthesized and its crystal structure is determined by single X-ray diffraction. There exist two molecules in the asymmetric unit. The dihedral angle between the benzene and anthracene moiety of the molecule A and B is 86.51(12)° and 76.42(13)°, respectively. No classical hydrogen bonds are observed and only van der Waals forces stabilize the crystal packing.

Crystal structure of tin(IV) chloride octa­hydrate

PubMed Central

Hennings, Erik; Schmidt, Horst; Voigt, Wolfgang

2014-01-01

The title compound, [SnCl4(H2O)2]·6H2O, was crystallized according to the solid–liquid phase diagram at lower temperatures. It is built-up of SnCl4(H2O)2 octa­hedral units (point group symmetry 2) and lattice water mol­ecules. An intricate three-dimensional network of O—H⋯O and O—H⋯Cl hydrogen bonds between the complex molecules and the lattice water molecules is formed in the crystal structure. PMID:25552971

A small molecule fusion inhibitor of dengue virus.

PubMed

Poh, Mee Kian; Yip, Andy; Zhang, Summer; Priestle, John P; Ma, Ngai Ling; Smit, Jolanda M; Wilschut, Jan; Shi, Pei-Yong; Wenk, Markus R; Schul, Wouter

2009-12-01

The dengue virus envelope protein plays an essential role in viral entry by mediating fusion between the viral and host membranes. The crystal structure of the envelope protein shows a pocket (located at a "hinge" between Domains I and II) that can be occupied by ligand n-octyl-beta-D-glucoside (betaOG). Compounds blocking the betaOG pocket are thought to interfere with conformational changes in the envelope protein that are essential for fusion. Two fusion assays were developed to examine the anti-fusion activities of compounds. The first assay measures the cellular internalization of propidium iodide upon membrane fusion. The second assay measures the protease activity of trypsin upon fusion between dengue virions and trypsin-containing liposomes. We performed an in silico virtual screening for small molecules that can potentially bind to the betaOG pocket and tested these candidate molecules in the two fusion assays. We identified one compound that inhibits dengue fusion in both assays with an IC(50) of 6.8 microM and reduces viral titers with an EC(50) of 9.8 microM. Time-of-addition experiments showed that the compound was only active when present during viral infection but not when added 1h later, in agreement with a mechanism of action through fusion inhibition.

Structural, spectroscopic and electronic properties of hydrogen-bonded water molecules in crystals. Ab initio calculations and experimental data of MC1 2· n(H,D) 2O, M = Sr or Ba

NASA Astrophysics Data System (ADS)

Möller, H.; Niu, J. E.; Lutz, H. D.; Schwarz, W. H. E.

1997-12-01

Structural, spectroscopic and electronic properties of (more or less deuterated) water molecules in the crystal fields of SrCl 2·2H 2O, SrCl 2·H 2O and BaCl 2·H 2O, previously investigated by experimental techniques, were calculated by ab initio SCF-MP methods. The H 2O molecules of each compound are asymmetrically surrounded by three adjacent chloride ions, one hydrogen atom being attached to a nearby Cl -, the other less perturbed hydrogen atom bridging the two less near Cl -. The diversity of structural and spectroscopic features found experimentally, for instance the trends from free H 2O to H 2O in BaCl 2·H 2OSrCl 2·H 2OSrCl 2·2H 2O, are well reproduced by the model calculations, which provide the correct assignment and physical interpretation. The differences between the compounds and the asymmetry of the hydrate water molecules can be rationalized with the help of crystal fields. The crystal environment expands the internuclear distances of H 2O by up to 3 pm. The change of vibrational frequencies can be explained qualitatively by only taking the coupling and anharmonicity of the free water molecule and its modified structure in the crystals into account. The infra-red intensities, however, are strongly influenced by the electronic polarization.

Design and structure of stapled peptides binding to estrogen receptors.

PubMed

Phillips, Chris; Roberts, Lee R; Schade, Markus; Bazin, Richard; Bent, Andrew; Davies, Nichola L; Moore, Rob; Pannifer, Andrew D; Pickford, Andrew R; Prior, Stephen H; Read, Christopher M; Scott, Andrew; Brown, David G; Xu, Bin; Irving, Stephen L

2011-06-29

Synthetic peptides that specifically bind nuclear hormone receptors offer an alternative approach to small molecules for the modulation of receptor signaling and subsequent gene expression. Here we describe the design of a series of novel stapled peptides that bind the coactivator peptide site of estrogen receptors. Using a number of biophysical techniques, including crystal structure analysis of receptor-stapled peptide complexes, we describe in detail the molecular interactions and demonstrate that all-hydrocarbon staples modulate molecular recognition events. The findings have implications for the design of stapled peptides in general.

Immune Checkpoint PD-1/PD-L1: Is There Life Beyond Antibodies?

PubMed

Konstantinidou, Markella; Zarganes-Tzitzikas, Tryfon; Magiera-Mularz, Katarzyna; Holak, Tad A; Dömling, Alexander

2018-04-23

The PD-1/PD-L1 interaction has emerged as a significant target in cancer immunotherapy. Current medications include monoclonal antibodies, which have shown impressive clinical results in the treatment of several types of tumors. The cocrystal structure of human PD-1 and PD-L1 is expected to be a valuable starting point for the design of novel inhibitors, along with the recent crystal structures with monoclonal antibodies, small molecules, and macrocycles. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Entropic Description of Gas Hydrate Ice-Liquid Equilibrium via Enhanced Sampling of Coexisting Phases

NASA Astrophysics Data System (ADS)

Małolepsza, Edyta; Kim, Jaegil; Keyes, Tom

2015-05-01

Metastable β ice holds small guest molecules in stable gas hydrates, so its solid-liquid equilibrium is of interest. However, aqueous crystal-liquid transitions are very difficult to simulate. A new molecular dynamics algorithm generates trajectories in a generalized N P T ensemble and equilibrates states of coexisting phases with a selectable enthalpy. With replicas spanning the range between β ice and liquid water, we find the statistical temperature from the enthalpy histograms and characterize the transition by the entropy, introducing a general computational procedure for first-order transitions.

Discovery of a Potent Class of PI3Kα Inhibitors with Unique Binding Mode via Encoded Library Technology (ELT).

PubMed

Yang, Hongfang; Medeiros, Patricia F; Raha, Kaushik; Elkins, Patricia; Lind, Kenneth E; Lehr, Ruth; Adams, Nicholas D; Burgess, Joelle L; Schmidt, Stanley J; Knight, Steven D; Auger, Kurt R; Schaber, Michael D; Franklin, G Joseph; Ding, Yun; DeLorey, Jennifer L; Centrella, Paolo A; Mataruse, Sibongile; Skinner, Steven R; Clark, Matthew A; Cuozzo, John W; Evindar, Ghotas

2015-05-14

In the search of PI3K p110α wild type and H1047R mutant selective small molecule leads, an encoded library technology (ELT) campaign against the desired target proteins was performed which led to the discovery of a selective chemotype for PI3K isoforms from a three-cycle DNA encoded library. An X-ray crystal structure of a representative inhibitor from this chemotype demonstrated a unique binding mode in the p110α protein.

Discovery of a Potent Class of PI3Kα Inhibitors with Unique Binding Mode via Encoded Library Technology (ELT)

PubMed Central

2015-01-01

In the search of PI3K p110α wild type and H1047R mutant selective small molecule leads, an encoded library technology (ELT) campaign against the desired target proteins was performed which led to the discovery of a selective chemotype for PI3K isoforms from a three-cycle DNA encoded library. An X-ray crystal structure of a representative inhibitor from this chemotype demonstrated a unique binding mode in the p110α protein. PMID:26005528

Entropic description of gas hydrate ice/liquid equilibrium via enhanced sampling of coexisting phases

DOE PAGES

Malolepsza, Edyta; Kim, Jaegil; Keyes, Tom

2015-04-28

Metastable β ice holds small guest molecules in stable gas hydrates, so its solid/liquid equilibrium is of interest. However, aqueous crystal/liquid transitions are very difficult to simulate. A new MD algorithm generates trajectories in a generalized NPT ensemble and equilibrates states of coexisting phases with a selectable enthalpy. Furthermore, with replicas spanning the range between β ice and liquid water we find the statistical temperature from the enthalpy histograms and characterize the transition by the entropy, introducing a general computational procedure for first-order transitions.

Organic crystal-binding peptides: morphology control and one-pot formation of protein-displaying organic crystals

NASA Astrophysics Data System (ADS)

Niide, Teppei; Ozawa, Kyohei; Nakazawa, Hikaru; Oliveira, Daniel; Kasai, Hitoshi; Onodera, Mari; Asano, Ryutaro; Kumagai, Izumi; Umetsu, Mitsuo

2015-11-01

Crystalline assemblies of fluorescent molecules have different functional properties than the constituent monomers, as well as unique optical characteristics that depend on the structure, size, and morphological homogeneity of the crystal particles. In this study, we selected peptides with affinity for the surface of perylene crystal particles by exposing a peptide-displaying phage library in aqueous solution to perylene crystals, eluting the surface-bound phages by means of acidic desorption or liquid-liquid extraction, and amplifying the obtained phages in Escherichia coli. One of the perylene-binding peptides, PeryBPb1: VQHNTKYSVVIR, selected by this biopanning procedure induced perylene molecules to form homogenous planar crystal nanoparticles by means of a poor solvent method, and fusion of the peptide to a fluorescent protein enabled one-pot formation of protein-immobilized crystalline nanoparticles. The nanoparticles were well-dispersed in aqueous solution, and Förster resonance energy transfer from the perylene crystals to the fluorescent protein was observed. Our results show that the crystal-binding peptide could be used for simultaneous control of perylene crystal morphology and dispersion and protein immobilization on the crystals.Crystalline assemblies of fluorescent molecules have different functional properties than the constituent monomers, as well as unique optical characteristics that depend on the structure, size, and morphological homogeneity of the crystal particles. In this study, we selected peptides with affinity for the surface of perylene crystal particles by exposing a peptide-displaying phage library in aqueous solution to perylene crystals, eluting the surface-bound phages by means of acidic desorption or liquid-liquid extraction, and amplifying the obtained phages in Escherichia coli. One of the perylene-binding peptides, PeryBPb1: VQHNTKYSVVIR, selected by this biopanning procedure induced perylene molecules to form homogenous planar crystal nanoparticles by means of a poor solvent method, and fusion of the peptide to a fluorescent protein enabled one-pot formation of protein-immobilized crystalline nanoparticles. The nanoparticles were well-dispersed in aqueous solution, and Förster resonance energy transfer from the perylene crystals to the fluorescent protein was observed. Our results show that the crystal-binding peptide could be used for simultaneous control of perylene crystal morphology and dispersion and protein immobilization on the crystals. Electronic supplementary information (ESI) available: Schematic representation of PeryBPb1-fused DsRed-Monomer, fluorescence spectra of perylene crystals and DsRed-Monomer, and emission spectra of DsRed-Monomer at various excitation wavelengths. See DOI: 10.1039/c5nr06471f

Chiral Crystallization of Ethylenediamine Sulfate

ERIC Educational Resources Information Center

Koby, Lawrence; Ningappa, Jyothi B.; Dakesssian, Maria; Cuccia, Louis A.

2005-01-01

The optimal conditions for the crystallization of achiral ethylenediamine sulfate into large chiral crystals that are ideal for polarimetry studies and observation using Polaroid sheets are presented. This experiment is an ideal undergraduate experiment, which clearly demonstrates the chiral crystallization of an achiral molecule.

Towards solution and refinement of organic crystal structures by fitting to the atomic pair distribution function

DOE Office of Scientific and Technical Information (OSTI.GOV)

Prill, Dragica; Juhas, Pavol; Billinge, Simon J. L.

2016-01-01

In this study, a method towards the solution and refinement of organic crystal structures by fitting to the atomic pair distribution function (PDF) is developed. Approximate lattice parameters and molecular geometry must be given as input. The molecule is generally treated as a rigid body. The positions and orientations of the molecules inside the unit cell are optimized starting from random values. The PDF is obtained from carefully measured X-ray powder diffraction data. The method resembles `real-space' methods for structure solution from powder data, but works with PDF data instead of the diffraction pattern itself. As such it may bemore » used in situations where the organic compounds are not long-range-ordered, are poorly crystalline, or nanocrystalline. The procedure was applied to solve and refine the crystal structures of quinacridone (β phase), naphthalene and allopurinol. In the case of allopurinol it was even possible to successfully solve and refine the structure in P1 with four independent molecules. As an example of a flexible molecule, the crystal structure of paracetamol was refined using restraints for bond lengths, bond angles and selected torsion angles. In all cases, the resulting structures are in excellent agreement with structures from single-crystal data.« less

Vibrational states of a water molecule in a nano-cavity of beryl crystal lattice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhukova, Elena S., E-mail: zhukovaelenka@gmail.com; Gorshunov, Boris P.; 1. Physikalisches Institut, Universität Stuttgart, Pfaffenwaldring 57, 70550 Stuttgart

2014-06-14

Low-energy excitations of a single water molecule are studied when confined within a nano-size cavity formed by the ionic crystal lattice. Optical spectra are measured of manganese doped beryl single crystal Mn:Be{sub 3}Al{sub 2}Si{sub 6}O{sub 18}, that contains water molecules individually isolated in 0.51 nm diameter voids within the crystal lattice. Two types of orientation are distinguished: water-I molecules have their dipole moments aligned perpendicular to the c axis and dipole moments of water-II molecules are parallel to the c-axis. The optical conductivity σ(ν) and permittivity ε{sup ′}(ν) spectra are recorded in terahertz and infrared ranges, at frequencies from severalmore » wavenumbers up to ν = 7000 cm{sup −1}, at temperatures 5–300 K and for two polarizations, when the electric vector E of the radiation is parallel and perpendicular to the c-axis. Comparative experiments on as-grown and on dehydrated samples allow to identify the spectra of σ(ν) and ε{sup ′}(ν) caused exclusively by water molecules. In the infrared range, well-known internal modes ν{sub 1}, ν{sub 2}, and ν{sub 3} of the H{sub 2}O molecule are observed for both polarizations, indicating the presence of water-I and water-II molecules in the crystal. Spectra recorded below 1000 cm{sup −1} reveal a rich set of highly anisotropic features in the low-energy response of H{sub 2}O molecule in a crystalline nano-cavity. While for E∥c only two absorption peaks are detected, at ∼90 cm{sup −1} and ∼160 cm{sup −1}, several absorption bands are discovered for E⊥c, each consisting of narrower resonances. The bands are assigned to librational (400–500 cm{sup −1}) and translational (150–200 cm{sup −1}) vibrations of water-I molecule that is weakly coupled to the nano-cavity “walls.” A model is presented that explains the “fine structure” of the bands by a splitting of the energy levels due to quantum tunneling between the minima in a six-well potential relief felt by a molecule within the cavity.« less

Biomass-derived oxygenate reforming on Pt(111): A demonstration of surface science using D-glucose and its model surrogate glycolaldehyde

NASA Astrophysics Data System (ADS)

McManus, Jesse R.; Yu, Weiting; Salciccioli, Michael; Vlachos, Dionisios G.; Chen, Jingguang G.; Vohs, John M.

2012-12-01

Molecules derived from cellulosic biomass, such as glucose, represent an important renewable feedstock for the production of hydrogen and hydrocarbon-based fuels and chemicals. Development of efficient catalysts for their reformation into useful products is needed; however, this requires a detailed understanding of their adsorption and reaction on catalytically active transition metal surfaces. In this paper we demonstrate that the standard surface science techniques routinely used to characterize the reaction of small molecules on metals are also amenable for use in studying the adsorption and reaction of complex biomass-derivatives on single crystal metal surfaces. In particular, Temperature Programmed Desorption (TPD) and High Resolution Electron Energy Loss Spectroscopy (HREELS) combined with Density Functional Theory (DFT) calculations were used to elucidate the adsorption configuration of D-glucose and glycolaldehye on Pt(111). Both molecules were found to adsorb in an η1 aldehyde configuration partially validating the use of simple, functionally-equivalent model compounds for surface studies of cellulosic oxygenates.

Investigating protein-protein interaction surfaces using a reduced stereochemical and electrostatic model.

PubMed

Warwicker, J

1989-03-20

A method of calculating the electrostatic potential energy between two molecules, using finite difference potential, is presented. A reduced charge set is used so that the interaction energy can be calculated as the two static molecules explore their full six-dimensional configurational space. The energies are contoured over surfaces fixed to each molecule with an interactive computer graphics program. For two crystal structures (trypsin-trypsin inhibitor and anti-lysozyme Fab-lysozyme), it is found that the complex corresponds to highly favourable interacting regions in the contour plots. These matches arise from a small number of protruding basic residues interacting with enhanced negative potential in each case. The redox pair cytochrome c peroxidase-cytochrome c exhibits an extensive favourably interacting surface within which a possible electron transfer complex may be defined by an increased electrostatic complementarity, but a decreased electrostatic energy. A possible substrate transfer configuration for the glycolytic enzyme pair glyceraldehyde phosphate dehydrogenase-phosphoglycerate kinase is presented.

Enhanced Hydrate Nucleation Near the Limit of Stability.

PubMed

Jimenez-Angeles, Felipe; Firoozabadi, Abbas

2015-03-30

Clathrate hydrates are crystalline structures composed of small guest molecules trapped into cages formed by hydrogen-bonded water molecules. In hydrate nucleation, water and the guest molecules may stay in a metastable fluid mixture for a long period. Metastability is broken if the concentration of the guest is above certain limit. We perform molecular dynamics (MD) simulations of supersaturated water-propane solutions close to the limit of stability. We show that hydrate nucleation can be very fast in a very narrow range of composition at moderate temperatures. Propane density fluctuations near the fluid-fluid demixing are coupled with crystallization producing en- hanced nucleation rates. This is the first report of propane-hydrate nucleation by MD simulations. We observe motifs of the crystalline structure II in line with experiments and new hydrate cages not reported in the literature. Our study relates nucleation to the fluid-fluid spinodal decomposition and demonstration that the enhanced nucleation phenomenon is more general than short range attractive interactions as suggested in nucleation of proteins.

Host-guest interaction between Acridine orange molecules and AFI or CHA zeolite crystals

NASA Astrophysics Data System (ADS)

Chen, Yanping; Fu, Ling; Xu, Xintong; Li, Irene Ling; Ruan, Shuangchen; Jian, Dunliang; Zhai, Jianpang

2017-02-01

Acridine orange (AO) molecules were incorporated in AlPO4-5, SAPO-5 and SAPO-47 single crystals by vapor-phase diffusion method. Polarized absorption spectra show that AO molecules are well aligned by the one-dimensional channel systems of AlPO4-5 and SAPO-5 matrices. While the orientation of AO molecules in SAPO-47 crystals is diverse owing to the three-dimensional cage structure of chabazite (structure code CHA). The absorption peak and emission peak of AO/SAPO-5 blue shift compared with that of AO/AlPO4-5 because the channel environment changes from non-polar medium to polar medium when Si substituted in the framework of AlPO4-5. The greater blue shift in absorption band and emission band of AO/SAPO-47 are expected to originate from the polar channel medium and smaller channel size of SAPO-47.

Hydrogen Bonding: Between Strengthening the Crystal Packing and Improving Solubility of Three Haloperidol Derivatives.

PubMed

Saluja, Hardeep; Mehanna, Ahmed; Panicucci, Riccardo; Atef, Eman

2016-06-01

The purpose of this study is to confirm the impact of polar functional groups on inter and intra-molecular hydrogen bonding in haloperidol (HP) and droperidol (DP) and, hence, their effects on dissolution using a new approach. To confirm our theory, a new molecule: deshydroxy-haloperidol (DHP) was designed and its synthesis was requested from a contract laboratory. The molecule was then studied and compared to DP and HP. Unlike DHP, both the HP and DP molecules have hydrogen donor groups, therefore, DHP was used to confirm the relative effects of the hydrogen donor group on solubility and crystal packing. The solid dispersions of the three structurally related molecules: HP, DP, and DHP were prepared using PVPK30, and characterized using XRPD and IR. A comparative dissolution study was carried out in aqueous medium. The absence of a hydrogen bonding donor group in DHP resulted in an unexpected increase in its aqueous solubility and dissolution rate from solid dispersion, which is attributed to weaker crystal pack. The increased dissolution rate of HP and DP from solid dispersions is attributed to drug-polymer hydrogen bonding that interferes with the drug-drug intermolecular hydrogen bonding and provides thermodynamic stability of the dispersed drug molecules. The drug-drug intermolecular hydrogen bond is the driving force for precipitation and crystal packing.

Topographically induced homeotropic alignment of liquid crystals on self-assembled opal crystals.

PubMed

Kumar, Pankaj; Oh, Su Yeon; Baliyan, Vijay K; Kundu, Sudarshan; Lee, Seung Hee; Kang, Shin-Woong

2018-04-02

The surface of multilayered opal crystals resulted in homeotropic alignment of liquid crystal (LC), originated from the surface topography of opal crystals rather than a chemical nature of the nanoparticles. The polar anchoring energy (5.51 × 10 -5 J/m 2 ) of the crystal surface for nematic LC molecules was in a similar range to the conventional polyimide alignment layer (2.11 × 10 -5 J/m 2 ) used for commercial applications. The critical length scale for anchoring transition was approximately Lw = ~1 μm. If a diameter of particle d < 1 μm for opal crystals, LC molecules preferred to anchor vertically to the surface to minimize elastic free energy of bulk LCs. The LC favored a planar anchoring if d > 1 μm. The results provide crucial insights to understand the homeotropic alignment of LCs on solid surfaces and therefore offer opportunities to develop novel materials for a vertical alignment of LCs.

RNA Crystallization

NASA Technical Reports Server (NTRS)

Golden, Barbara L.; Kundrot, Craig E.

2003-01-01

RNA molecules may be crystallized using variations of the methods developed for protein crystallography. As the technology has become available to syntheisize and purify RNA molecules in the quantities and with the quality that is required for crystallography, the field of RNA structure has exploded. The first consideration when crystallizing an RNA is the sequence, which may be varied in a rational way to enhance crystallizability or prevent formation of alternate structures. Once a sequence has been designed, the RNA may be synthesized chemically by solid-state synthesis, or it may be produced enzymatically using RNA polymerase and an appropriate DNA template. Purification of milligram quantities of RNA can be accomplished by HPLC or gel electrophoresis. As with proteins, crystallization of RNA is usually accomplished by vapor diffusion techniques. There are several considerations that are either unique to RNA crystallization or more important for RNA crystallization. Techniques for design, synthesis, purification, and crystallization of RNAs will be reviewed here.

Microgravity

NASA Image and Video Library

2000-05-05

This computer graphic depicts the relative complexity of crystallizing large proteins in order to study their structures through x-ray crystallography. Insulin is a vital protein whose structure has several subtle points that scientists are still trying to determine. Large molecules such as insuline are complex with structures that are comparatively difficult to understand. For comparison, a sugar molecule (which many people have grown as hard crystals in science glass) and a water molecule are shown. These images were produced with the Macmolecule program. Photo credit: NASA/Marshall Space Flight Center (MSFC)

Screening of detergents for solubilization, purification and crystallization of membrane proteins: a case study on succinate:ubiquinone oxidoreductase from Escherichia coli

PubMed Central

Shimizu, Hironari; Nihei, Coh-ichi; Inaoka, Daniel Ken; Mogi, Tatushi; Kita, Kiyoshi; Harada, Shigeharu

2008-01-01

Succinate:ubiquinone oxidoreductase (SQR) was solubilized and purified from Escherichia coli inner membranes using several different detergents. The number of phospholipid molecules bound to the SQR molecule varied greatly depending on the detergent combination that was used for the solubilization and purification. Crystallization conditions were screened for SQR that had been solubilized and purified using 2.5%(w/v) sucrose monolaurate and 0.5%(w/v) Lubrol PX, respectively, and two different crystal forms were obtained in the presence of detergent mixtures composed of n-alkyl-oligoethylene glycol monoether and n-alkyl-maltoside. Crystallization took place before detergent phase separation occurred and the type of detergent mixture affected the crystal form. PMID:18765923

Modeling solute clustering in the diffusion layer around a growing crystal.

PubMed

Shiau, Lie-Ding; Lu, Yung-Fang

2009-03-07

The mechanism of crystal growth from solution is often thought to consist of a mass transfer diffusion step followed by a surface reaction step. Solute molecules might form clusters in the diffusion step before incorporating into the crystal lattice. A model is proposed in this work to simulate the evolution of the cluster size distribution due to the simultaneous aggregation and breakage of solute molecules in the diffusion layer around a growing crystal in the stirred solution. The crystallization of KAl(SO(4))(2)12H(2)O from aqueous solution is studied to illustrate the effect of supersaturation and diffusion layer thickness on the number-average degree of clustering and the size distribution of solute clusters in the diffusion layer.

Screening of detergents for solubilization, purification and crystallization of membrane proteins: a case study on succinate:ubiquinone oxidoreductase from Escherichia coli.

PubMed

Shimizu, Hironari; Nihei, Coh-ichi; Inaoka, Daniel Ken; Mogi, Tatushi; Kita, Kiyoshi; Harada, Shigeharu

2008-09-01

Succinate:ubiquinone oxidoreductase (SQR) was solubilized and purified from Escherichia coli inner membranes using several different detergents. The number of phospholipid molecules bound to the SQR molecule varied greatly depending on the detergent combination that was used for the solubilization and purification. Crystallization conditions were screened for SQR that had been solubilized and purified using 2.5%(w/v) sucrose monolaurate and 0.5%(w/v) Lubrol PX, respectively, and two different crystal forms were obtained in the presence of detergent mixtures composed of n-alkyl-oligoethylene glycol monoether and n-alkyl-maltoside. Crystallization took place before detergent phase separation occurred and the type of detergent mixture affected the crystal form.

Gold nanoparticle-sensitized quartz crystal microbalance sensor for rapid and highly selective determination of Cu(II) ions.

PubMed

Jin, Yulong; Huang, Yanyan; Liu, Guoquan; Zhao, Rui

2013-09-21

A novel quartz crystal microbalance (QCM) sensor for rapid, highly selective and sensitive detection of copper ions was developed. As a signal amplifier, gold nanoparticles (Au NPs) were self-assembled onto the surface of the sensor. A simple dip-and-dry method enabled the whole detection procedure to be accomplished within 20 min. High selectivity of the sensor towards copper ions is demonstrated by both individual and coexisting assays with interference ions. This gold nanoparticle mediated amplification allowed a detection limit down to 3.1 μM. Together with good repeatability and regeneration, the QCM sensor was also applied to the analysis of copper contamination in drinking water. This work provides a flexible method for fabricating QCM sensors for the analysis of important small molecules in environmental and biological samples.

Structural Properties, Order–Disorder Phenomena, and Phase Stability of Orotic Acid Crystal Forms

PubMed Central

2016-01-01

Orotic acid (OTA) is reported to exist in the anhydrous (AH), monohydrate (Hy1), and dimethyl sulfoxide monosolvate (SDMSO) forms. In this study we investigate the (de)hydration/desolvation behavior, aiming at an understanding of the elusive structural features of anhydrous OTA by a combination of experimental and computational techniques, namely, thermal analytical methods, gravimetric moisture (de)sorption studies, water activity measurements, X-ray powder diffraction, spectroscopy (vibrational, solid-state NMR), crystal energy landscape, and chemical shift calculations. The Hy1 is a highly stable hydrate, which dissociates above 135 °C and loses only a small part of the water when stored over desiccants (25 °C) for more than one year. In Hy1, orotic acid and water molecules are linked by strong hydrogen bonds in nearly perfectly planar arranged stacked layers. The layers are spaced by 3.1 Å and not linked via hydrogen bonds. Upon dehydration the X-ray powder diffraction and solid-state NMR peaks become broader, indicating some disorder in the anhydrous form. The Hy1 stacking reflection (122) is maintained, suggesting that the OTA molecules are still arranged in stacked layers in the dehydration product. Desolvation of SDMSO, a nonlayer structure, results in the same AH phase as observed upon dehydrating Hy1. Depending on the desolvation conditions, different levels of order–disorder of layers present in anhydrous OTA are observed, which is also suggested by the computed low energy crystal structures. These structures provide models for stacking faults as intergrowth of different layers is possible. The variability in anhydrate crystals is of practical concern as it affects the moisture dependent stability of AH with respect to hydration. PMID:26741914

Crystal structure of 3-[(4-benzyl-piperazin-1-yl)meth-yl]-5-(thio-phen-2-yl)-2,3-di-hydro-1,3,4-oxa-diazole-2-thione.

PubMed

Al-Omary, Fatmah A M; El-Emam, Ali A; Ghabbour, Hazem A; Chidan Kumar, C S; Quah, Ching Kheng; Fun, Hoong-Kun

2015-03-01

The title 1,3,4-oxa-diazole-2-thione derivative, C18H20N4OS2, crystallized with two independent mol-ecules (A and B) in the asymmetric unit. The 2-thienyl rings in both mol-ecules are rotationally disordered over two orientations by approximately 180° about the single C-C bond that connects it to the oxa-diazole thione ring; the ratios of site occupancies for the major and minor components were fixed in the structure refinement at 0.8:0.2 and 0.9:0.1 in mol-ecules A and B, respectively. The 1,3,4-oxa-diazole-2-thione ring forms dihedral angles of 7.71 (16), 10.0 (11) and 77.50 (12)° (mol-ecule A), and 6.5 (3), 6.0 (9) and 55.30 (12)° (mol-ecule B) with the major and minor parts of the disordered thio-phene ring and the mean plane of the adjacent piperazine ring, respectively, resulting in approximately V-shaped conformations for the mol-ecules. The piperazine ring in both mol-ecules adopts a chair conformation. The terminal benzene ring is inclined towards the mean plane of the piperazine ring with N-C-C-C torsion angles of -58.2 (3) and -66.2 (3)° in mol-ecules A and B, respectively. In the crystal, no inter-molecular hydrogen bonds are observed. The crystal packing features short S⋯S contacts [3.4792 (9) Å] and π-π inter-actions [3.661 (3), 3.664 (11) and 3.5727 (10) Å], producing a three-dimensional network.

Crystal Nucleation in Liquids: Open Questions and Future Challenges in Molecular Dynamics Simulations

PubMed Central

2016-01-01

The nucleation of crystals in liquids is one of nature’s most ubiquitous phenomena, playing an important role in areas such as climate change and the production of drugs. As the early stages of nucleation involve exceedingly small time and length scales, atomistic computer simulations can provide unique insights into the microscopic aspects of crystallization. In this review, we take stock of the numerous molecular dynamics simulations that, in the past few decades, have unraveled crucial aspects of crystal nucleation in liquids. We put into context the theoretical framework of classical nucleation theory and the state-of-the-art computational methods by reviewing simulations of such processes as ice nucleation and the crystallization of molecules in solutions. We shall see that molecular dynamics simulations have provided key insights into diverse nucleation scenarios, ranging from colloidal particles to natural gas hydrates, and that, as a result, the general applicability of classical nucleation theory has been repeatedly called into question. We have attempted to identify the most pressing open questions in the field. We believe that, by improving (i) existing interatomic potentials and (ii) currently available enhanced sampling methods, the community can move toward accurate investigations of realistic systems of practical interest, thus bringing simulations a step closer to experiments. PMID:27228560

Fragment-based screen against HIV protease.

PubMed

Perryman, Alexander L; Zhang, Qing; Soutter, Holly H; Rosenfeld, Robin; McRee, Duncan E; Olson, Arthur J; Elder, John E; Stout, C David

2010-03-01

We have employed a fragment-based screen against wild-type (NL4-3) HIV protease (PR) using the Active Sight fragment library and X-ray crystallography. The experiments reveal two new binding sites for small molecules. PR was co-crystallized with fragments, or crystals were soaked in fragment solutions, using five crystal forms, and 378 data sets were collected to 2.3-1.3 A resolution. Fragment binding induces a distinct conformation and specific crystal form of TL-3 inhibited PR during co-crystallization. One fragment, 2-methylcyclohexanol, binds in the 'exo site' adjacent to the Gly(16)Gly(17)Gln(18)loop where the amide of Gly(17)is a specific hydrogen bond donor, and hydrophobic contacts occur with the side chains of Lys(14)and Leu(63). Another fragment, indole-6-carboxylic acid, binds on the 'outside/top of the flap' via hydrophobic contacts with Trp(42), Pro(44), Met(46), and Lys(55), a hydrogen bond with Val(56), and a salt-bridge with Arg(57). 2-acetyl-benzothiophene also binds at this site. This study is the first fragment-based crystallographic screen against HIV PR, and the first time that fragments were screened against an inhibitor-bound drug target to search for compounds that both bind to novel sites and stabilize the inhibited conformation of the target.

Fragment-Based Screen against HIV Protease

PubMed Central

Perryman, A. L.; Zhang, Q.; Soutter, H. H.; Rosenfeld, R.; McRee, D. E.; Olson, A. J.; Elder, J. E.; Stout, C. D.

2009-01-01

We have employed a fragment-based screen against wild-type (NL4-3) HIV protease (PR) using the Active Sight fragment library and X-ray crystallography. The experiments reveal two new binding sites for small molecules. PR was co-crystallized with fragments, or crystals were soaked in fragment solutions, using five crystal forms, and 378 data sets were collected to 2.3-1.3 Å resolution. Fragment binding induces a distinct conformation and specific crystal form of TL-3 inhibited PR during co-crystallization. One fragment, 2-methylcyclohexanol, binds in the ‘exo site’ adjacent to the Gly16Gly17Gln18 loop where the amide of Gly17 is a specific hydrogen bond donor, and hydrophobic contacts occur with the side chains of Lys14 and Leu63. Another fragment, indole-6-carboxylic acid, binds on the ‘outside/top of the flap’ via hydrophobic contacts with Trp42, Pro44, Met46, and Lys55, a hydrogen bond with Val56, and a salt-bridge with Arg57. 2-acetyl-benzothiophene also binds at this site. This study is the first fragment-based crystallographic screen against HIV PR, and the first time that fragments were screened against an inhibitor-bound drug target to search for compounds that both bind to novel sites and stabilize the inhibited conformation of the target. PMID:20659109

Protein purification in multicompartment electrolyzers for crystal growth of r-DNA products in microgravity

NASA Technical Reports Server (NTRS)

Righetti, Pier Giorgio; Casale, Elena; Carter, Daniel; Snyder, Robert S.; Wenisch, Elisabeth; Faupel, Michel

1990-01-01

Recombinant-DNA (deoxyribonucleic acid) (r-DNA) proteins, produced in large quantities for human consumption, are now available in sufficient amounts for crystal growth. Crystallographic analysis is the only method now available for defining the atomic arrangements within complex biological molecules and decoding, e.g., the structure of the active site. Growing protein crystals in microgravity has become an important aspect of biology in space, since crystals that are large enough and of sufficient quality to permit complete structure determinations are usually obtained. However even small amounts of impurities in a protein preparation are anathema for the growth of a regular crystal lattice. A multicompartment electrolyzer with isoelectric, immobiline membranes, able to purify large quantities of r-DNA proteins is described. The electrolyzer consists of a stack of flow cells, delimited by membranes of very precise isoelectric point (pI, consisting of polyacrylamide supported by glass fiber filters containing Immobiline buffers and titrants to uniquely define a pI value) and very high buffering power, able to titrate all proteins tangent or crossing such membranes. By properly selecting the pI values of two membranes delimiting a flow chamber, a single protein can be kept isoelectric in a single flow chamber and thus, be purified to homogeneity (by the most stringent criterion, charge homogeneity).

Crystal Nucleation in Liquids: Open Questions and Future Challenges in Molecular Dynamics Simulations.

PubMed

Sosso, Gabriele C; Chen, Ji; Cox, Stephen J; Fitzner, Martin; Pedevilla, Philipp; Zen, Andrea; Michaelides, Angelos

2016-06-22

The nucleation of crystals in liquids is one of nature's most ubiquitous phenomena, playing an important role in areas such as climate change and the production of drugs. As the early stages of nucleation involve exceedingly small time and length scales, atomistic computer simulations can provide unique insights into the microscopic aspects of crystallization. In this review, we take stock of the numerous molecular dynamics simulations that, in the past few decades, have unraveled crucial aspects of crystal nucleation in liquids. We put into context the theoretical framework of classical nucleation theory and the state-of-the-art computational methods by reviewing simulations of such processes as ice nucleation and the crystallization of molecules in solutions. We shall see that molecular dynamics simulations have provided key insights into diverse nucleation scenarios, ranging from colloidal particles to natural gas hydrates, and that, as a result, the general applicability of classical nucleation theory has been repeatedly called into question. We have attempted to identify the most pressing open questions in the field. We believe that, by improving (i) existing interatomic potentials and (ii) currently available enhanced sampling methods, the community can move toward accurate investigations of realistic systems of practical interest, thus bringing simulations a step closer to experiments.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kuz'mina, L. G., E-mail: kuzmina@igic.ras.ru; Vedernikov, A. I.; Sazonov, S. K.

The crystal packing of a number of styryl dyes of the pyridine series is analyzed. The structures of three dyes and three [2 + 2] photocycloaddition (PCA) products, 1,2,3,4-tetrasubstituted cyclobutanes, obtained in single crystals are determined by X-ray diffraction. Stacks of planar organic cations are characteristic of styryl dye packings. The proceeding of the PCA reaction as a single crystal-to-single crystal transformation in the syn head-to-head stacks is in principle impossible. The syn head-to-tail stacking packings are favorable for the PCA reactions resulting in the centrosymmetric rctt isomers of cyclobutane. The stacking packings, in which molecules are related by themore » twofold axes (the anti arrangement of molecules), are also favorable for PCA in single crystals. In this case, the products are the rtct isomers of cyclobutane. The presence of the I{sup -} counterions in a packing is a factor impeding the PCA reaction, because the secondary I-H-C bonds increase the rigidity of the crystal lattice. The conditions necessary for proceeding the PCA reactions in styryl dyes as single crystal-to-single crystal processes are as follows: (1) the stacks split into pairs of organic cations (dimers) with the d distances within 4.2 A in a dimer and d exceeding 4.2 A between the dimers; and (2) the dimers are surrounded by flexible shells consisting of anions, solvate molecules, or flexible moieties of the organic cations themselves.« less

Crystal growth, characterization and theoretical studies of 4-aminopyridinium picrate

NASA Astrophysics Data System (ADS)

Aditya Prasad, A.; Muthu, K.; Rajasekar, M.; Meenatchi, V.; Meenakshisundaram, S. P.

2015-01-01

Single crystals of 4-aminopyridinium picrate (APP) were grown by slow evaporation of a mixed solvent system methanol-acetone (1:1, v/v) containing equimolar quantities of 4-aminopyridine and picric acid. Structure is elucidated by single crystal XRD analysis and the crystal belongs to monoclinic system with four molecules in the unit cell (space group P21/c) and the cell parameter values are, a = 8.513 Å (±0.015), b = 11.33 Å (±0.02), c = 14.33 Å (±0.03) and β = 104.15° (±0.019), V = 1340 A3 (±6) with refined R factors R1 = 0.0053 and wR2 = 0.0126. The electron density mapping is interpreted to find coordinates for each atom in the crystallized molecules. The various functional groups present in the molecule are confirmed by FT-IR analysis. UV-visible spectral analysis was used to determine the band gap energy of 4-aminopyridinium picrate. Powder X-ray diffraction pattern reveals the crystallinity of the as-grown crystal and it closely resembles the simulated XRD from the single crystal XRD analysis. Scanning electron microscopy reveals the surface morphology of the grown crystal. Optimized geometry is derived by Hartree-Fock theory calculations and the first-order molecular hyperpolarizability (β), theoretically calculated bond length, bond angles and excited state energy from theoretical UV-vis spectrum were estimated.

Generation of crystal structures using known crystal structures as analogues

PubMed Central

Cole, Jason C.; Groom, Colin R.; Read, Murray G.; Giangreco, Ilenia; McCabe, Patrick; Reilly, Anthony M.; Shields, Gregory P.

2016-01-01

This analysis attempts to answer the question of whether similar molecules crystallize in a similar manner. An analysis of structures in the Cambridge Structural Database shows that the answer is yes – sometimes they do, particularly for single-component structures. However, one does need to define what we mean by similar in both cases. Building on this observation we then demonstrate how this correlation between shape similarity and packing similarity can be used to generate potential lattices for molecules with no known crystal structure. Simple intermolecular interaction potentials can be used to minimize these potential lattices. Finally we discuss the many limitations of this approach. PMID:27484374

Rational design of crystal contact-free space in protein crystals for analyzing spatial distribution of motions within protein molecules.

PubMed

Matsuoka, Rei; Shimada, Atsushi; Komuro, Yasuaki; Sugita, Yuji; Kohda, Daisuke

2016-03-01

Contacts with neighboring molecules in protein crystals inevitably restrict the internal motions of intrinsically flexible proteins. The resultant clear electron densities permit model building, as crystallographic snapshot structures. Although these still images are informative, they could provide biased pictures of the protein motions. If the mobile parts are located at a site lacking direct contacts in rationally designed crystals, then the amplitude of the movements can be experimentally analyzed. We propose a fusion protein method, to create crystal contact-free space (CCFS) in protein crystals and to place the mobile parts in the CCFS. Conventional model building fails when large amplitude motions exist. In this study, the mobile parts appear as smeared electron densities in the CCFS, by suitable processing of the X-ray diffraction data. We applied the CCFS method to a highly mobile presequence peptide bound to the mitochondrial import receptor, Tom20, and a catalytically relevant flexible segment in the oligosaccharyltransferase, AglB. These two examples demonstrated the general applicability of the CCFS method to the analysis of the spatial distribution of motions within protein molecules. © 2016 The Protein Society.

How to assign a (3 + 1)-dimensional superspace group to an incommensurately modulated biological macromolecular crystal

PubMed Central

2017-01-01

Periodic crystal diffraction is described using a three-dimensional (3D) unit cell and 3D space-group symmetry. Incommensurately modulated crystals are a subset of aperiodic crystals that need four to six dimensions to describe the observed diffraction pattern, and they have characteristic satellite reflections that are offset from the main reflections. These satellites have a non-integral relationship to the primary lattice and require q vectors for processing. Incommensurately modulated biological macromolecular crystals have been frequently observed but so far have not been solved. The authors of this article have been spearheading an initiative to determine this type of crystal structure. The first step toward structure solution is to collect the diffraction data making sure that the satellite reflections are well separated from the main reflections. Once collected they can be integrated and then scaled with appropriate software. Then the assignment of the superspace group is needed. The most common form of modulation is in only one extra direction and can be described with a (3 + 1)D superspace group. The (3 + 1)D superspace groups for chemical crystallographers are fully described in Volume C of International Tables for Crystallography. This text includes all types of crystallographic symmetry elements found in small-molecule crystals and can be difficult for structural biologists to understand and apply to their crystals. This article provides an explanation for structural biologists that includes only the subset of biological symmetry elements and demonstrates the application to a real-life example of an incommensurately modulated protein crystal. PMID:28808437

Nanoparticles in liquid crystals, and liquid crystals in nanoparticles

NASA Astrophysics Data System (ADS)

de Pablo, Juan

2015-03-01

Liquid crystals are remarkably sensitive to interfacial interactions. Small perturbations at a liquid crystal interface, for example, can be propagated over relatively long length scales, thereby providing the basis for a wide range of applications that rely on amplification of molecular events into macroscopic observables. Our recent research efforts have focused on the reverse phenomenon; that is, we have sought to manipulate the interfacial assembly of nanoparticles or the organization of surface active molecules by controlling the structure of a liquid crystal. This presentation will consist of a review of the basic principles that are responsible for liquid crystal-mediated interactions, followed by demonstrations of those principles in the context of two types of systems. In the first, a liquid crystal is used to direct the assembly of nanoparticles; through a combination of molecular and continuum models, it is found that minute changes in interfacial energy and particle size lead to liquid-crystal induced attractions that can span multiple orders of magnitude. Theoretical predictions are confirmed by experimental observations, which also suggest that LC-mediated assembly provides an effective means for fabrication of plasmonic devices. In the second type of system, the structure of a liquid crystal is controlled by confinement in submicron droplets. The morphology of the liquid crystal in a drop depends on a delicate balance between bulk and interfacial contributions to the free energy; that balance can be easily perturbed by adsorption of analytes or nanoparticles at the interface, thereby providing the basis for development of hierarchical assembly of responsive, anisotropic materials. Theoretical predictions also indicate that the three-dimensional order of a liquid crystal can be projected onto a two-dimensional interface, and give rise to novel nanostructures that are not found in simple isotropic fluids.

Crystal structure of Rv2258c from Mycobacterium tuberculosis H37Rv, an S-adenosyl-l-methionine-dependent methyltransferase.

PubMed

Im, Ha Na; Kim, Hyoun Sook; An, Doo Ri; Jang, Jun Young; Kim, Jieun; Yoon, Hye-Jin; Yang, Jin Kuk; Suh, Se Won

2016-03-01

The Mycobacterium tuberculosis Rv2258c protein is an S-adenosyl-L-methionine (SAM)-dependent methyltransferase (MTase). Here, we have determined its crystal structure in three forms: a ligand-unbound form, a binary complex with sinefungin (SFG), and a binary complex with S-adenosyl-L-homocysteine (SAH). The monomer structure of Rv2258c consists of two domains which are linked by a long α-helix. The N-terminal domain is essential for dimerization and the C-terminal domain has the Class I MTase fold. Rv2258c forms a homodimer in the crystal, with the N-terminal domains facing each other. It also exists as a homodimer in solution. A DALI structural similarity search with Rv2258c reveals that the overall structure of Rv2258c is very similar to small-molecule SAM-dependent MTases. Rv2258c interacts with the bound SFG (or SAH) in an extended conformation maintained by a network of hydrogen bonds and stacking interactions. Rv2258c has a relatively large hydrophobic cavity for binding of the methyl-accepting substrate, suggesting that bulky nonpolar molecules with aromatic rings might be targeted for methylation by Rv2258c in M. tuberculosis. However, the ligand-binding specificity and the biological role of Rv2258c remain to be elucidated due to high variability of the amino acid residues defining the substrate-binding site. Copyright © 2016 Elsevier Inc. All rights reserved.

Measuring order in disordered systems and disorder in ordered systems: Random matrix theory for isotropic and nematic liquid crystals and its perspective on pseudo-nematic domains

NASA Astrophysics Data System (ADS)

Zhao, Yan; Stratt, Richard M.

2018-05-01

Surprisingly long-ranged intermolecular correlations begin to appear in isotropic (orientationally disordered) phases of liquid crystal forming molecules when the temperature or density starts to close in on the boundary with the nematic (ordered) phase. Indeed, the presence of slowly relaxing, strongly orientationally correlated, sets of molecules under putatively disordered conditions ("pseudo-nematic domains") has been apparent for some time from light-scattering and optical-Kerr experiments. Still, a fully microscopic characterization of these domains has been lacking. We illustrate in this paper how pseudo-nematic domains can be studied in even relatively small computer simulations by looking for order-parameter tensor fluctuations much larger than one would expect from random matrix theory. To develop this idea, we show that random matrix theory offers an exact description of how the probability distribution for liquid-crystal order parameter tensors converges to its macroscopic-system limit. We then illustrate how domain properties can be inferred from finite-size-induced deviations from these random matrix predictions. A straightforward generalization of time-independent random matrix theory also allows us to prove that the analogous random matrix predictions for the time dependence of the order-parameter tensor are similarly exact in the macroscopic limit, and that relaxation behavior of the domains can be seen in the breakdown of the finite-size scaling required by that random-matrix theory.

Solvation and Aggregation of Meta-Aminobenzoic Acid in Water: Density Functional Theory and Molecular Dynamics Study

PubMed Central

Gaines, Etienne

2018-01-01

Meta-aminobenzoic acid, an important model system in the study of polymorphism and crystallization of active pharmaceutical ingredients, exist in water in both the nonionic (mABA) and zwitterionic (mABA±) forms. However, the constituent molecules of the polymorph that crystallizes from aqueous solutions are zwitterionic. This study reports atomistic simulations of the events surrounding the early stage of crystal nucleation of meta-aminobenzoic acid from aqueous solutions. Ab initio molecular dynamics was used to simulate the hydration of mABA± and mABA and to quantify the interaction of these molecules with the surrounding water molecules. Density functional theory calculations were conducted to determine the low-lying energy conformers of meta-aminobenzoic acid dimers and to compute the Gibbs free energies in water of nonionic, (mABA)2, zwitterionic, (mABA±)2, and nonionic-zwitterionic, (mABA)(mABA±), species. Classical molecular dynamics simulations of mixed mABA–mABA± aqueous solutions were carried out to examine the aggregation of meta-aminobenzoic acid. According to these simulations, the selective crystallization of the polymorphs whose constituent molecules are zwitterionic is driven by the formation of zwitterionic dimers in solution, which are thermodynamically more stable than (mABA)2 and (mABA)(mABA±) pairs. This work represents a paradigm of the role of molecular processes during the early stages of crystal nucleation in affecting polymorph selection during crystallization from solution. PMID:29360788

Elastic Organic Crystals of a Fluorescent π-Conjugated Molecule.

PubMed

Hayashi, Shotaro; Koizumi, Toshio

2016-02-18

An elastic organic crystal of a π-conjugated molecule has been fabricated. A large fluorescent single crystal of 1,4-bis[2-(4-methylthienyl)]-2,3,5,6-tetrafluorobenzene (over 1 cm long) exhibited a fibril lamella morphology based on slip-stacked molecular wires, and it was found to be a remarkably elastic crystalline material. The straight crystal was capable of bending more than 180° under applied stress and then quickly reverted to its original shape upon relaxation. In addition, the fluorescence quantum yield of the crystal was about twice that of the compound in THF solution. Mechanical bending-relaxation resulted in reversible change of the morphology and fluorescence. This research offers a more general approach to flexible crystals as a promising new family of organic semiconducting materials. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Epistatic mutations in PUMA BH3 drive an alternate binding mode to potently and selectively inhibit anti-apoptotic Bfl-1

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jenson, Justin M.; Ryan, Jeremy A.; Grant, Robert A.

Overexpression of anti-apoptotic Bcl-2 family proteins contributes to cancer progression and confers resistance to chemotherapy. Small molecules that target Bcl-2 are used in the clinic to treat leukemia, but tight and selective inhibitors are not available for Bcl-2 paralog Bfl-1. Guided by computational analysis, we designed variants of the native BH3 motif PUMA that are > 150-fold selective for Bfl-1 binding. The designed peptides potently trigger disruption of the mitochondrial outer membrane in cells dependent on Bfl-1, but not in cells dependent on other anti-apoptotic homologs. High-resolution crystal structures show that designed peptide FS2 binds Bfl-1 in a shifted geometry,more » relative to PUMA and other binding partners, due to a set of epistatic mutations. FS2 modified with an electrophile reacts with a cysteine near the peptide-binding groove to augment specificity. Designed Bfl-1 binders provide reagents for cellular profiling and leads for developing enhanced and cell-permeable peptide or small-molecule inhibitors.« less

Structural integration in hypoxia-inducible factors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wu, Dalei; Potluri, Nalini; Lu, Jingping

The hypoxia-inducible factors (HIFs) coordinate cellular adaptations to low oxygen stress by regulating transcriptional programs in erythropoiesis, angiogenesis and metabolism. These programs promote the growth and progression of many tumours, making HIFs attractive anticancer targets. Transcriptionally active HIFs consist of HIF-alpha and ARNT (also called HIF-1 beta) subunits. Here we describe crystal structures for each of mouse HIF-2 alpha-ARNT and HIF-1 alpha-ARNT heterodimers in states that include bound small molecules and their hypoxia response element. A highly integrated quaternary architecture is shared by HIF-2 alpha-ARNT and HIF-1 alpha-ARNT, wherein ARNT spirals around the outside of each HIF-alpha subunit. Five distinctmore » pockets are observed that permit small-molecule binding, including PAS domain encapsulated sites and an interfacial cavity formed through subunit heterodimerization. The DNA-reading head rotates, extends and cooperates with a distal PAS domain to bind hypoxia response elements. HIF-alpha mutations linked to human cancers map to sensitive sites that establish DNA binding and the stability of PAS domains and pockets.« less

On macromolecular refinement at subatomic resolution with interatomic scatterers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Afonine, Pavel V., E-mail: pafonine@lbl.gov; Grosse-Kunstleve, Ralf W.; Adams, Paul D.

2007-11-01

Modelling deformation electron density using interatomic scatters is simpler than multipolar methods, produces comparable results at subatomic resolution and can easily be applied to macromolecules. A study of the accurate electron-density distribution in molecular crystals at subatomic resolution (better than ∼1.0 Å) requires more detailed models than those based on independent spherical atoms. A tool that is conventionally used in small-molecule crystallography is the multipolar model. Even at upper resolution limits of 0.8–1.0 Å, the number of experimental data is insufficient for full multipolar model refinement. As an alternative, a simpler model composed of conventional independent spherical atoms augmented bymore » additional scatterers to model bonding effects has been proposed. Refinement of these mixed models for several benchmark data sets gave results that were comparable in quality with the results of multipolar refinement and superior to those for conventional models. Applications to several data sets of both small molecules and macromolecules are shown. These refinements were performed using the general-purpose macromolecular refinement module phenix.refine of the PHENIX package.« less

Relativistic nuclear magnetic resonance J-coupling with ultrasoft pseudopotentials and the zeroth-order regular approximation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Green, Timothy F. G., E-mail: tim.green@materials.ox.ac.uk; Yates, Jonathan R., E-mail: jonathan.yates@materials.ox.ac.uk

2014-06-21

We present a method for the first-principles calculation of nuclear magnetic resonance (NMR) J-coupling in extended systems using state-of-the-art ultrasoft pseudopotentials and including scalar-relativistic effects. The use of ultrasoft pseudopotentials is allowed by extending the projector augmented wave (PAW) method of Joyce et al. [J. Chem. Phys. 127, 204107 (2007)]. We benchmark it against existing local-orbital quantum chemical calculations and experiments for small molecules containing light elements, with good agreement. Scalar-relativistic effects are included at the zeroth-order regular approximation level of theory and benchmarked against existing local-orbital quantum chemical calculations and experiments for a number of small molecules containing themore » heavy row six elements W, Pt, Hg, Tl, and Pb, with good agreement. Finally, {sup 1}J(P-Ag) and {sup 2}J(P-Ag-P) couplings are calculated in some larger molecular crystals and compared against solid-state NMR experiments. Some remarks are also made as to improving the numerical stability of dipole perturbations using PAW.« less

[In situ Raman spectroscopic observation of micro-processes of methane hydrate formation and dissociation].

PubMed

Liu, Chang-Ling; Ye, Yu-Guang; Meng, Qing-Guo; Lü, Wan-Jun; Wang, Fei-Fei

2011-06-01

Micro laser Raman spectroscopic technique was used for in situ observation of the micro-processes of methane hydrate formed and decomposed in a high pressure transparent capillary. The changes in clathrate structure of methane hydrate were investigated during these processes. The results show that, during hydrate formation, the Raman peak (2 917 cm(-1)) of methane gas gradually splits into two peaks (2 905 and 2 915 cm(-1)) representing large and small cages, respectively, suggesting that the dissolved methane molecules go into two different chemical environments. In the meantime, the hydrogen bonds interaction is strengthened because water is changing from liquid to solid state gradually. As a result, the O-H stretching vibrations of water shift to lower wavenumber. During the decomposition process of methane hydrates, the Raman peaks of the methane molecules both in the large and small cages gradually clear up, and finally turn into a single peak of methane gas. The experimental results show that laser Raman spectroscopy can accurately demonstrate some relevant information of hydrate crystal structure changes during the formation and dissociation processes of methane hydrate.

Epistatic mutations in PUMA BH3 drive an alternate binding mode to potently and selectively inhibit anti-apoptotic Bfl-1

PubMed Central

Jenson, Justin M; Ryan, Jeremy A; Grant, Robert A; Letai, Anthony; Keating, Amy E

2017-01-01

Overexpression of anti-apoptotic Bcl-2 family proteins contributes to cancer progression and confers resistance to chemotherapy. Small molecules that target Bcl-2 are used in the clinic to treat leukemia, but tight and selective inhibitors are not available for Bcl-2 paralog Bfl-1. Guided by computational analysis, we designed variants of the native BH3 motif PUMA that are > 150-fold selective for Bfl-1 binding. The designed peptides potently trigger disruption of the mitochondrial outer membrane in cells dependent on Bfl-1, but not in cells dependent on other anti-apoptotic homologs. High-resolution crystal structures show that designed peptide FS2 binds Bfl-1 in a shifted geometry, relative to PUMA and other binding partners, due to a set of epistatic mutations. FS2 modified with an electrophile reacts with a cysteine near the peptide-binding groove to augment specificity. Designed Bfl-1 binders provide reagents for cellular profiling and leads for developing enhanced and cell-permeable peptide or small-molecule inhibitors. DOI: http://dx.doi.org/10.7554/eLife.25541.001 PMID:28594323

Dielectric relaxation of guest molecules in a clathrate structure of syndiotactic polystyrene.

PubMed

Urakawa, Osamu; Kaneko, Fumitoshi; Kobayashi, Hideo

2012-12-13

Structure and dynamics of semicrystalline polymer films composed of syndiotactic polystyrene (sPS) and 2-butanone were examined through X-ray diffraction, polarized FTIR, and dielectric relaxation measurements. The X-ray and FTIR measurements revealed its crystal structure to be δ-clathrate containing 2-butanone molecules inside. The carbonyl group of 2-butanone in the crystal was found to orient preferentially parallel to the ac plane of the crystal through the polarized ATR FTIR measurements. Dielectric measurements were also conducted on these film samples to see only the relaxation dynamics of 2-butanone thanks to the high dielectric intensity of 2-butanone compared to sPS. Two relaxation modes denoted by slow and fast modes appeared. The former was assigned to the motion of 2-butanone molecules entrapped in the cavities of the crystalline (δ-form) and the latter to those in the amorphous region. We focused on the slow mode in order to elucidate the specific dynamics of the guest molecule confined in the crystalline region. The relaxation time of the slow mode was about 4 orders of magnitude longer than that of liquid 2-butanone. This suggests that the dynamics of guest molecules is highly restricted due to the high barrier to conformational and/or orientational change of the guest molecule in the cavity of δ-crystal. Furthermore, the dielectric intensity Δε of the slow mode was much smaller than the one calculated from that of bulk liquid 2-butanone and the guest concentration in the crystalline region (the intensity was only 10% of the estimated value from the bulk liquid data). This result also indicates that the free rotational motion of 2-butanone molecules is restricted inside the crystal. This will be consistently related to the weak uniplanar orientation of the carbonyl group of 2-butanone parallel to the ac plane revealed by the X-ray and polarized ATR FTIR measurements.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bolotin, B. M., E-mail: bolotin70@yandex.ru; Mikhlina, Ya. A.; Arkhipova, S. A.

The crystal and molecular structures of two crystal forms (pale yellow form 1 and yellow form 2) of N-[2-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)phenyl]naphthalene-2-sulfonamide (Orlyum White 520T), which is an organic luminophore with an anomalously high Stokes shift, were determined. Crystal 2 is a solvate with para-xylene. Crystal 1 is a solvent-free form. The molecular geometry in crystal 1 differs from that in 2 only in the orientation of the SO{sub 2}Ar substituent. The bond-length distribution in the planar moiety of the molecule in crystal 1 is virtually identical to that in 2, but the bonds in the NH-SO{sub 2}Ar-bearing benzene ring in crystal 1more » are systematically longer than the corresponding bonds in crystal 2. This fact can be attributed to the crystal-packing effects. In 2 the molecules form stacked dimers with {pi}-stacking interactions between two planar conjugated tricyclic systems. The charge transfer in this system accounts for the intensification of the color of these crystals and the observed difference in the optical properties of 1 and 2.« less

Early stages of zeolite growth

NASA Astrophysics Data System (ADS)

Kumar, Sandeep

Zeolites are crystalline nonporous aluminosilicates with important applications in separation, purification, and adsorption of liquid and gaseous molecules. However, an ability to tailor the zeolite microstructure, such as particle size/shape and pore-size, to make it benign for specific application requires control over nucleation and particle growth processes. But, the nucleation and crystallization mechanisms of zeolites are not fully understood. In this context, the synthesis of an all-silica zeolite with MFI-type framework has been studied extensively as a model system. Throughout chapters 2, 4 and 5, MFI growth process has been investigated by small-angle x-ray scattering (SAXS) and transmission electron microscopy (TEM). Of fundamental importance is the role of nanoparticles (~5 nm), which are present in the precursor sol, in MFI nucleation and crystallization. Formation of amorphous aggregates and their internal restructuring are concluded as essential steps in MFI nucleation. Early stage zeolite particles have disordered and less crystalline regions within, which indicates the role of structurally distributed population of nanoparticles in growth. Faceting occurs after the depletion of nanoparticles. The chapter 6 presents growth studies in silica sols prepared by using a dimer of tertaprpylammonium (TPA) and reports that MFI nucleation and crystallization are delayed with a more pronounced delay in crystal growth.

Slotted Photonic Crystal Sensors

PubMed Central

Scullion, Mark G.; Krauss, Thomas F.; Di Falco, Andrea

2013-01-01

Optical biosensors are increasingly being considered for lab-on-a-chip applications due to their benefits such as small size, biocompatibility, passive behaviour and lack of the need for fluorescent labels. The light guiding mechanisms used by many of them results in poor overlap of the optical field with the target molecules, reducing the maximum sensitivity achievable. This review article presents a new platform for optical biosensors, namely slotted photonic crystals, which provide higher sensitivities due to their ability to confine, spatially and temporally, the optical mode peak within the analyte itself. Loss measurements showed values comparable to standard photonic crystals, confirming their ability to be used in real devices. A novel resonant coupler was designed, simulated, and experimentally tested, and was found to perform better than other solutions within the literature. Combining with cavities, microfluidics and biological functionalization allowed proof-of-principle demonstrations of protein binding to be carried out. Higher sensitivities were observed in smaller structures than possible with most competing devices reported in the literature. This body of work presents slotted photonic crystals as a realistic platform for complete on-chip biosensing; addressing key design, performance and application issues, whilst also opening up exciting new ideas for future study. PMID:23503295

Molecular self-assembly for biological investigations and nanoscale lithography

NASA Astrophysics Data System (ADS)

Cheunkar, Sarawut

Small, diffusible molecules when recognized by their binding partners, such as proteins and antibodies, trigger enzymatic activity, cell communication, and immune response. Progress in analytical methods enabling detection, characterization, and visualization of biological dynamics at the molecular level will advance our exploration of complex biological systems. In this dissertation, analytical platforms were fabricated to capture membrane-associated receptors, which are essential proteins in cell signaling pathways. The neurotransmitter serotonin and its biological precursor were immobilized on gold substrates coated with self-assembled monolayers (SAMs) of oligo(ethylene glycol)alkanethiols and their reactive derivatives. The SAM-coated substrates present the biologically selective affinity of immobilized molecules to target native membrane-associated receptors. These substrates were also tested for biospecificity using antibodies. In addition, small-molecule-functionalized platforms, expressing neurotransmitter pharmacophores, were employed to examine kinetic interactions between G-protein-coupled receptors and their associated neurotransmitters. The binding interactions were monitored using a quartz crystal microbalance equipped with liquid-flow injection. The interaction kinetics of G-protein-coupled serotonin 1A receptor and 5-hydroxytyptophan-functionalized surfaces were studied in a real-time, label-free environment. Key binding parameters, such as equilibrium dissociation constants, binding rate constants, and dissociative half-life, were extracted. These parameters are critical for understanding and comparing biomolecular interactions in modern biomedical research. By integrating self-assembly, surface functionalization, and nanofabrication, small-molecule microarrays were created for high-throughput screening. A hybrid soft-lithography, called microcontact insertion printing, was used to pattern small molecules at the dilute scales necessary for highly selective biorecognition. By carefully tuning the polar surface energy of polymeric stamps, problems associated with patterning hydrophilic tether molecules inserted into hydrophilic preformed SAMs are surmounted. The patterned substrates presenting neurotransmitter precursors selectively capture membrane-associated receptors. These advances provide new avenues for fabricating small-molecule arrays. Furthermore, a novel strategy based on a conventional microcontact printing, called chemical lift-off lithography, was invented to overcome the micrometer-scale resolution limits of molecular ink diffusion in soft lithography. Self-assembled monolayers of hydroxyl-terminated alkanethiols, preformed on gold substrates, were selectively removed by oxygen-plasma-treated polymeric stamps in a subtractive stamping process with high pattern fidelity. The covalent interactions formed at the stamp-substrate interface are believed to be responsible for removing not only alkanethiol molecules but also a monolayer of gold atoms from the substrates. A variety of high-resolution patterned features were fabricated, and stamps were cleaned and reused many times without feature deterioration. The remaining SAMs acted as resists for etching exposed gold features. Monolayer backfilling into lifted-off areas enabled patterned protein capture, and 40-nanometer chemical patterns were achieved.

Racemic crystallography of synthetic protein enantiomers used to determine the X-ray structure of plectasin by direct methods

PubMed Central

Mandal, Kalyaneswar; Pentelute, Brad L; Tereshko, Valentina; Thammavongsa, Vilasak; Schneewind, Olaf; Kossiakoff, Anthony A; Kent, Stephen B H

2009-01-01

We describe the use of racemic crystallography to determine the X-ray structure of the natural product plectasin, a potent antimicrobial protein recently isolated from fungus. The protein enantiomers l-plectasin and d-plectasin were prepared by total chemical synthesis; interestingly, l-plectasin showed the expected antimicrobial activity, while d-plectasin was devoid of such activity. The mirror image proteins were then used for racemic crystallization. Synchrotron X-ray diffraction data were collected to atomic resolution from a racemic plectasin crystal; the racemate crystallized in the achiral centrosymmetric space group with one l-plectasin molecule and one d-plectasin molecule forming the unit cell. Dimer-like intermolecular interactions between the protein enantiomers were observed, which may account for the observed extremely low solvent content (13%–15%) and more highly ordered nature of the racemic crystals. The structure of the plectasin molecule was well defined for all 40 amino acids and was generally similar to the previously determined NMR structure, suggesting minimal impact of the crystal packing on the plectasin conformation. PMID:19472324

Molecular dynamics approach to probe PKCβII-ligand interactions and influence of crystal water molecules on these interactions.

PubMed

Grewal, Baljinder K; Bhat, Jyotsna; Sobhia, Masilamani Elizabeth

2015-01-01

PKCβII is a potential target for therapeutic intervention against pandemic diabetic complications. Present study probes the molecular interactions of PKCβII with its clinically important ligands, viz. ruboxistaurin, enzastaurin and co-crystallized ligand, 2-methyl-1H-indol-3-yl-BIM-1. The essentials of PKCβII-ligand interaction, crystal water-induced alterations in these interactions and key interacting flexible residues are analyzed. Computational methodologies, viz. molecular docking and molecular simulation coupled with molecular mechanics-Poisson-Boltzmann surface area and generalized born surface area (MM-PB[GB]SA) are employed. The structural changes in the presence and absence of crystal water molecules in PKCβII ATP binding site residues, and its interaction with bound ligand, are identified. Difference in interaction of selective and nonselective ligand with ATP binding site residues of PKCβII is reported. The study showed that the nonbonding interactions contribute significantly in PKCβII-ligand binding and presence of crystal water molecules affects the interactions. The findings of present work may integrate the new aspects in the drug design process of PKCβII inhibitors.

Analysis of holographic polymer-dispersed liquid crystals (HPDLCs) for tunable low frequency diffractive optical elements recording

NASA Astrophysics Data System (ADS)

Fernández, R.; Gallego, S.; Márquez, A.; Francés, J.; Martínez, F. J.; Pascual, I.; Beléndez, A.

2018-02-01

Holographic polymer dispersed liquid crystals (HPDLCs) are the result of the optimization of the photopolymer fabrication techniques. They are made by recording in a photopolymerization induced phase separation process (PIPS) in which the liquid crystal molecules diffuse to dark zones in the diffraction grating originated. Thanks to the addition of liquid crystal molecules to the composition, this material has a dynamic behavior by reorientation of the liquid crystal molecules applying an electrical field. In this sense, it is possible to use this material to make dynamic devices. In this work, we study the behavior of this material working in low frequencies with different spatial periods of blazed gratings, a sharp profile whose recording is possible thanks to the addition of a Holoeye LCoS-Pluto spatial light modulator with a resolution of 1920 × 1080 pixels (HD) and a pixel size of 8 × 8 μm2. This device allows us to have an accurate and dynamic control of the phase and amplitude of the recording beam.

On a fast calculation of structure factors at a subatomic resolution.

PubMed

Afonine, P V; Urzhumtsev, A

2004-01-01

In the last decade, the progress of protein crystallography allowed several protein structures to be solved at a resolution higher than 0.9 A. Such studies provide researchers with important new information reflecting very fine structural details. The signal from these details is very weak with respect to that corresponding to the whole structure. Its analysis requires high-quality data, which previously were available only for crystals of small molecules, and a high accuracy of calculations. The calculation of structure factors using direct formulae, traditional for 'small-molecule' crystallography, allows a relatively simple accuracy control. For macromolecular crystals, diffraction data sets at a subatomic resolution contain hundreds of thousands of reflections, and the number of parameters used to describe the corresponding models may reach the same order. Therefore, the direct way of calculating structure factors becomes very time expensive when applied to large molecules. These problems of high accuracy and computational efficiency require a re-examination of computer tools and algorithms. The calculation of model structure factors through an intermediate generation of an electron density [Sayre (1951). Acta Cryst. 4, 362-367; Ten Eyck (1977). Acta Cryst. A33, 486-492] may be much more computationally efficient, but contains some parameters (grid step, 'effective' atom radii etc.) whose influence on the accuracy of the calculation is not straightforward. At the same time, the choice of parameters within safety margins that largely ensure a sufficient accuracy may result in a significant loss of the CPU time, making it close to the time for the direct-formulae calculations. The impact of the different parameters on the computer efficiency of structure-factor calculation is studied. It is shown that an appropriate choice of these parameters allows the structure factors to be obtained with a high accuracy and in a significantly shorter time than that required when using the direct formulae. Practical algorithms for the optimal choice of the parameters are suggested.

NMR crystallography of campho[2,3-c]pyrazole (Z' = 6): combining high-resolution 1H-13C solid-state MAS NMR spectroscopy and GIPAW chemical-shift calculations.

PubMed

Webber, Amy L; Emsley, Lyndon; Claramunt, Rosa M; Brown, Steven P

2010-09-30

(1)H-(13)C two-dimensional magic-angle spinning (MAS) solid-state NMR correlation spectra, recorded with the MAS-J-HMQC experiment, are presented for campho[2,3-c]pyrazole. For each (13)C moiety, there are six resonances associated with the six distinct molecules in the asymmetric unit cell (Z' = 6). The one-bond C-H correlations observed in the 2D (1)H-(13)C MAS-J-HMQC spectra allow the experimental determination of the (1)H and (13)C chemical shifts associated with the separate CH, CH(2), and CH(3) groups. (1)H and (13)C chemical shifts calculated by using the GIPAW (Gauge Including Projector Augmented Waves) plane-wave pseudopotential approach are presented. Calculations for the whole unit cell (12 × 29 = 348 atoms, with geometry optimization of all atoms) allow the assignment of the experimental (1)H and (13)C chemical shifts to the six distinct molecules. The calculated chemical shifts for the full crystal structure are compared with those for isolated molecules as extracted from the geometry-optimized crystal structure. In this way, the effect of intermolecular interactions on the observed chemical shifts is quantified. In particular, the calculations are sufficiently precise to differentiate the small (<1 ppm) differences between the (1)H chemical shifts of the six resonances associated with each distinct CH or CH(2) moiety.

Insights on the mechanism of action of immunostimulants in relation to their pharmacological potency. The effects of imidazoquinolines on TLR8.

PubMed

Kubli-Garfias, Carlos; Vázquez-Ramírez, Ricardo; Trejo-Muñoz, Cynthia; Berber, Arturo

2017-01-01

Imidazoquinolines are powerful immunostimulants (IMMS) that function through Toll-like receptors, particularly TLR7 and TLR8. In addition to enhancing the immune response, IMMS also function as antineoplastic drugs and vaccine adjuvants. These small compounds display almost the same molecular structure, except in some cases in which atom in position 1 varies and changes the imidazole characteristics. A variable acyclic side chain is also always attached at atom in position 2, while another chain may be attached at atom in position 1. These structural differences alter immune responses, such as the production of interferon regulatory factor and nuclear factor-κB (IRF-NFκB). In this work, quantum mechanics theory and computational chemistry methods were applied to study the physicochemical properties of the crystal binding site of TLR8 complexed with the following six IMMS molecules: Hybrid-2, XG1-236, DS802, CL075, CL097 and R848 (resiquimod). The PDB IDs of the crystals were: 4R6A, 4QC0, 4QBZ, 3W3K, 3W3J, and 3W3N respectively. Thus, were calculated, the total energy, solvation energy, interaction energy (instead of free energy) of the system and interaction energy of the polar region of the IMMS. Additionally, the dipole moment, electrostatic potential, polar surface, atomic charges, hydrogen bonds, and polar and hydrophobic interactions, among others, were assessed. Together, these properties revealed important differences among the six TLR8-immunostimulant complexes, reflected as different interaction energies and therefore different electrostatic environments and binding energies. Remarkably, the interaction energy of a defined polar region composed of the highly polarized N3, N5 atoms and the N11 amino group, acted as a polar pharmacophore that correlates directly with the reported immunopharmacological potency of the six complexed molecules. Based on these results, it was concluded that accurate physicochemical analysis of the crystal binding site could reveal the binding energy (measured as interaction energy) and associated molecular mechanism of action between IMMS and TLR8. These findings may facilitate the development and design of improved small molecules with IMMS properties that are targeted to the TLR system and have enhanced pharmacological effectiveness and reduced toxicity.

Insights on the mechanism of action of immunostimulants in relation to their pharmacological potency. The effects of imidazoquinolines on TLR8

PubMed Central

Kubli-Garfias, Carlos; Vázquez-Ramírez, Ricardo; Trejo-Muñoz, Cynthia; Berber, Arturo

2017-01-01

Imidazoquinolines are powerful immunostimulants (IMMS) that function through Toll-like receptors, particularly TLR7 and TLR8. In addition to enhancing the immune response, IMMS also function as antineoplastic drugs and vaccine adjuvants. These small compounds display almost the same molecular structure, except in some cases in which atom in position 1 varies and changes the imidazole characteristics. A variable acyclic side chain is also always attached at atom in position 2, while another chain may be attached at atom in position 1. These structural differences alter immune responses, such as the production of interferon regulatory factor and nuclear factor-κB (IRF-NFκB). In this work, quantum mechanics theory and computational chemistry methods were applied to study the physicochemical properties of the crystal binding site of TLR8 complexed with the following six IMMS molecules: Hybrid-2, XG1-236, DS802, CL075, CL097 and R848 (resiquimod). The PDB IDs of the crystals were: 4R6A, 4QC0, 4QBZ, 3W3K, 3W3J, and 3W3N respectively. Thus, were calculated, the total energy, solvation energy, interaction energy (instead of free energy) of the system and interaction energy of the polar region of the IMMS. Additionally, the dipole moment, electrostatic potential, polar surface, atomic charges, hydrogen bonds, and polar and hydrophobic interactions, among others, were assessed. Together, these properties revealed important differences among the six TLR8-immunostimulant complexes, reflected as different interaction energies and therefore different electrostatic environments and binding energies. Remarkably, the interaction energy of a defined polar region composed of the highly polarized N3, N5 atoms and the N11 amino group, acted as a polar pharmacophore that correlates directly with the reported immunopharmacological potency of the six complexed molecules. Based on these results, it was concluded that accurate physicochemical analysis of the crystal binding site could reveal the binding energy (measured as interaction energy) and associated molecular mechanism of action between IMMS and TLR8. These findings may facilitate the development and design of improved small molecules with IMMS properties that are targeted to the TLR system and have enhanced pharmacological effectiveness and reduced toxicity. PMID:28582454

Conservative Tryptophan Mutants of the Protein Tyrosine Phosphatase YopH Exhibit Impaired WPD-Loop Function and Crystallize with Divanadate Esters in Their Active Sites

PubMed Central

Moise, Gwendolyn; Gallup, Nathan M.; Alexandrova, Anastassia N.; Hengge, Alvan C.; Johnson, Sean J.

2016-01-01

Catalysis in protein tyrosine phosphatases (PTPs) involves movement of a protein loop called the WPD loop that brings a conserved aspartic acid into the active site to function as a general acid. Mutation of the tryptophan in the WPD loop of the PTP YopH to any other residue with a planar, aromatic side chain (phenylalanine, tyrosine, or histidine) disables general acid catalysis. Crystal structures reveal these conservative mutations leave this critical loop in a catalytically unproductive, quasi-open position. Although the loop positions in crystal structures are similar for all three conservative mutants, the reasons inhibiting normal loop closure differ for each mutant. In the W354F and W354Y mutants, steric clashes result from six-membered rings occupying the position of the five-membered ring of the native indole side chain. The histidine mutant dysfunction results from new hydrogen bonds stabilizing the unproductive position. The results demonstrate how even modest modifications can disrupt catalytically important protein dynamics. Crystallization of all the catalytically compromised mutants in the presence of vanadate gave rise to vanadate dimers at the active site. In W354Y and W354H, a divanadate ester with glycerol is observed. Such species have precedence in solution and are known from the small molecule crystal database. Such species have not been observed in the active site of a phosphatase, as a functional phosphatase would rapidly catalyze their decomposition. The compromised functionality of the mutants allows the trapping of species that undoubtedly form in solution and are capable of binding at the active sites of PTPs, and, presumably, other phosphatases. In addition to monomeric vanadate, such higher-order vanadium-based molecules are likely involved in the interaction of vanadate with PTPs in solution. PMID:26445170

Tandem differential mobility analysis-mass spectrometry reveals partial gas-phase collapse of the GroEL complex.

PubMed

Hogan, Christopher J; Ruotolo, Brandon T; Robinson, Carol V; Fernandez de la Mora, Juan

2011-04-07

A parallel-plate differential mobility analyzer and a time-of-flight mass spectrometer (DMA-MS) are used in series to measure true mobility in dry atmospheric pressure air for mass-resolved electrosprayed GroEL tetradecamers (14-mers; ~800 kDa). Narrow mobility peaks are found (2.6-2.9% fwhm); hence, precise mobilities can be obtained for these ions without collisional activation, just following their generation by electrospray ionization. In contrast to previous studies, two conformers are found with mobilities (Z) differing by ~5% at charge state z ~ 79. By extrapolating to small z, a common mobility/charge ratio Z(0)/z = 0.0117 cm(2) V(-1) s(-1) is found for both conformers. When interpreted as if the GroEL ion surface were smooth and the gas molecule-protein collisions were perfectly elastic and specular, this mobility yields an experimental collision cross section, Ω, 11% smaller than in an earlier measurement, and close to the cross section, A(C,crystal), expected for the crystal structure (determined by a geometric approximation). However, the similarity between Ω and A(C,crystal) does not imply a coincidence between the native and gas-phase structures. The nonideal nature of protein-gas molecule collisions introduces a drag enhancement factor, ξ = 1.36, with which the true cross section A(C) is related to Ω via A(C) = Ω/ξ. Therefore, A(C) for GroEL 14-mer ions determined by DMA measurements is 0.69A(C,crystal). The factor 1.36 used here is based on the experimental Stokes-Millikan equation, as well as on prior and new numerical modeling accounting for multiple scattering events via exact hard-sphere scattering calculations. Therefore, we conclude that the gas-phase structure of the GroEL complex as electrosprayed is substantially more compact than the corresponding X-ray crystal structure.

Carotenoid stoichiometry in the LH2 crystal: no spectral evidence for the presence of the second molecule in the alpha/beta-apoprotein dimer.

PubMed

Gall, Andrew; Gardiner, Alastair T; Cogdell, Richard J; Robert, Bruno

2006-07-10

In this work we have investigated the carotenoid-protein interactions in LH2 complexes of Rhodopseudomonas acidophila both in "free in solution" mixed-micelles and in three-dimensional crystals by Raman spectroscopy in resonance with the carotenoid (Car) molecules. We show that the Car molecules when bound to their binding pockets show no significant differences when the complexes are "free in solution" or packed in crystalline arrays. Furthermore, there is no significant wavelength dependence in the Raman spectrum of the Car molecules of LH2. This indicates that there is only one Car configuration in LH2 and thus only one molecule per alpha/beta-heterodimer.

Binary Colloidal Crystal Layers as Platforms for Surface Patterning of Puroindoline-Based Antimicrobial Peptides.

PubMed

Boden, Andrew; Bhave, Mrinal; Wang, Peng-Yuan; Jadhav, Snehal; Kingshott, Peter

2018-01-24

The ability of bacteria to form biofilms and the emergence of antibiotic-resistant strains have prompted the need to develop the next generation of antibacterial coatings. Antimicrobial peptides (AMPs) are showing promise as molecules that can address these issues, especially if used when immobilized as a surface coating. We present a method that explores how surface patterns together with the selective immobilization of an AMP called PuroA (FPVTWRWWKWWKG-NH 2 ) can be used to both kill bacteria and also as a tool to study bacterial attachment mechanisms. Surface patterning is achieved using stabilized self-assembled binary colloidal crystal (BCC) layers, allowing selective PuroA immobilization to carboxylated particles using N-(3-dimethylaminopropyl)-N'-ethyl carbodiimide (EDC) hydrochloride/N-hydroxysuccinimide (NHS) coupling chemistry. Covalent immobilization of PuroA was compared with physical adsorption (i.e., without the addition of EDC/NHS). The AMP-functionalized colloids and BCC layers were characterized by X-ray photoelectron spectroscopy, ζ potentials, and matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). Surface antimicrobial activity was assessed by viability assays using Escherichia coli. MALDI-TOF MS analysis revealed that although not all of PuroA was successfully covalently immobilized, a relatively low density of PuroA (1.93 × 10 13 molecules/cm 2 and 7.14 × 10 12 molecules/cm 2 for covalent and physical immobilization, respectively) was found to be sufficient at significantly decreasing the viability of E. coli by 70% when compared to that of control samples. The findings provide a proof of concept that BCC layers are a suitable platform for the patterned immobilization of AMPs and the importance of ascertaining the success of small-molecule grafting reactions using surface-MALDI, something that is often assumed to be successful in the field.

Ultracold molecule assembly with photonic crystals

NASA Astrophysics Data System (ADS)

Pérez-Ríos, Jesús; Kim, May E.; Hung, Chen-Lung

2017-12-01

Photoassociation (PA) is a powerful technique to synthesize molecules directly and continuously from cold and ultracold atoms into deeply bound molecular states. In freespace, however, PA efficiency is constrained by the number of spontaneous decay channels linking the initial excited molecular state to a sea of final (meta)stable rovibronic levels. Here, we propose a novel scheme based on molecules strongly coupled to a guided photonic mode in a photonic crystal waveguide that turns PA into a powerful tool for near deterministic formation of ultracold molecules in their ground rovibrational level. Our example shows a potential ground state molecule production efficiency > 90 % , and a saturation rate > {10}6 molecules per second. By combining state-of-the-art cold atomic and molecular physics with nanophotonic engineering, our scheme presents a novel experimental package for trapping, cooling, and optically manipulating ultracold molecules, thus opening up new possibilities in the direction of ultracold chemistry and quantum information.

Knowledge-Based Methods To Train and Optimize Virtual Screening Ensembles

PubMed Central

2016-01-01

Ensemble docking can be a successful virtual screening technique that addresses the innate conformational heterogeneity of macromolecular drug targets. Yet, lacking a method to identify a subset of conformational states that effectively segregates active and inactive small molecules, ensemble docking may result in the recommendation of a large number of false positives. Here, three knowledge-based methods that construct structural ensembles for virtual screening are presented. Each method selects ensembles by optimizing an objective function calculated using the receiver operating characteristic (ROC) curve: either the area under the ROC curve (AUC) or a ROC enrichment factor (EF). As the number of receptor conformations, N, becomes large, the methods differ in their asymptotic scaling. Given a set of small molecules with known activities and a collection of target conformations, the most resource intense method is guaranteed to find the optimal ensemble but scales as O(2N). A recursive approximation to the optimal solution scales as O(N2), and a more severe approximation leads to a faster method that scales linearly, O(N). The techniques are generally applicable to any system, and we demonstrate their effectiveness on the androgen nuclear hormone receptor (AR), cyclin-dependent kinase 2 (CDK2), and the peroxisome proliferator-activated receptor δ (PPAR-δ) drug targets. Conformations that consisted of a crystal structure and molecular dynamics simulation cluster centroids were used to form AR and CDK2 ensembles. Multiple available crystal structures were used to form PPAR-δ ensembles. For each target, we show that the three methods perform similarly to one another on both the training and test sets. PMID:27097522

Dimensionality Alteration and Intra- versus Inter-SBU Void Encapsulation in Zinc Phosphate Frameworks.

PubMed

Dar, Aijaz A; Bhat, Gulzar A; Murugavel, Ramaswamy

2016-06-06

4,4'-Bipyridine-N-oxide (BIPYMO, 1), a less commonly employed coordination polymer linker, has been used as a ditopic spacer to bridge double-four-ring (D4R) zinc phosphate clusters to form novel framework coordination polymers. Zinc phosphate framework compounds [Zn4(X-dipp)4(BIPYMO)2]n·2MeOH [X = H (2), Cl (3), Br (4), I (5); dipp = 2,6-diisopropylphenyl phosphate] have been obtained by treating a methanol solution of zinc acetate with X-dippH2 and BIPYMO (in a 1:1:1 molar ratio) at ambient conditions. Framework phosphates 2-5 can also be obtained by treating the preformed D4R cubanes [Zn(X-dipp)(DMSO)]4 with required quantities of BIPYMO in methanol. Single-crystal X-ray diffraction studies reveal that these framework solids are two-dimensional (2D) networks as opposed to the diamondoid networks obtained when the parent unoxidized 4,4'-bipyridine is used as the linker (Inorg. Chem. 2014, 53, 8959). The two types of voids (viz., smaller intra-D4R and larger inter-D4R) present in these framework solids can be utilized for different types of encapsulation processes. For example, the in situ generated 2D framework 2 encapsulates fluoride ions accompanied by a change in the dimensionality of the framework to yield {[(nC4H9)4N][F@(Zn4(dipp)4(BIPYMO)2)]}n (6). The three-dimensional framework 6 represents the first structurally characterized example of a fluoride-ion-encapsulated polymeric coordination compound or a metal-organic framework. The possibility of utilizing inter-D4R voids as hosts for small organic molecules has been explored by treating in situ generated 2 with a series of organic molecules of appropriate size. Framework 2 has been found to be a selective host for benzil and not for other structurally similar molecules such as benzoquinone, benzidine, anthracene, naphthalene, α-pyridoin, etc. The benzil-occluded isolated framework [benzil@{Zn4(dipp)4(BIPYMO)2}]n (7) has been isolated as single crystals, and its crystal structure determination revealed the binding of benzil molecules to the framework through strong π-π interactions.

Laser-induced multi-energy processing in diamond growth

NASA Astrophysics Data System (ADS)

Xie, Zhiqiang

Laser-induced multi-energy processing (MEP) introduces resonant vibrational excitations of precursor molecules to conventional chemical vapor deposition methods for material synthesis. In this study, efforts were extended to explore the capability of resonant vibrational excitations for promotion of energy efficiency in chemical reactions, for enhancement of diamond deposition, and for control of chemical reactions. The research project mainly focused on resonant vibrational excitations of precursor molecules using lasers in combustion flame deposition of diamond, which led to: 1) promotion of chemical reactions; 2) enhancement of diamond growth with higher growth rate and better crystallizations; 3) steering of chemical reactions which lead to preferential growth of {100}-oriented diamond films and crystals; and 4) mode-selective excitations of precursor molecules toward bond-selective control of chemical reactions. Diamond films and crystals were deposited in open air by combustion flame deposition through resonant vibrational excitations of precursor molecules, including ethylene (C2H4) and propylene (C3H 6). A kilowatt wavelength-tunable CO2 laser with spectral range from 9.2 to 10.9 microm was tuned to match vibrational modes of the precursor molecules. Resonant vibrational excitations of these molecules were achieved with high energy efficiency as compared with excitations using a common CO2 laser (fixed wavelength at 10.591microm). With resonant vibrational excitations, the diamond growth rate was increased; diamond quality was promoted; diamond crystals with lengths up to 5 mm were deposited in open air; preferential growth of {100}-oriented diamond films and single crystals was achieved; mode-selective excitations of precursor molecules were investigated toward control of chemical reactions. Optical emission spectroscopy (OES), mass spectrometry (MS), and molecular dynamic simulations were conducted to obtain an in-depth understanding of the resonant vibrational excitations. Species concentrations in flames without and with laser excitations under different wavelengths were investigated both experimentally and theoretically. Detection of C2, CH, and OH radicals, as well as CxHy species and their oxides (CxH yO) (x=1, 2; y=0˜5) using OES and MS, together with reaction pathway simulations, were used to explain the effect of vibrational excitations of precursor molecules on chemical reactions and on diamond depositions.