Search

The conjugate peak refinement algorithm and a quantum-mechanical potential are used to study the proton transfer (PT) reactions between adjacent sites exposed to water through the calculation the minimum energy pathways (MEPs). The MEP calculations have shown that the transition state is highly strained and has involved a supramolecular structure in which fluorescein and the interconnecting water molecules are covalently bonded together and the protons are shared between neighboring oxygens.

The catalysis mechanism in myosin II is investigated by using quantum mechanical/molecular mechanical reaction path calculations. The result has revealed a key element of the chemomehcanical coupling that underlies the motor cycle, such as the modulation of actin unbinding or binding in response to the ATP or ADP.P1 state of nucleotide-bound myosin.

Conjugate peak refinement analysis of the annexin V shows that Trp187 burial leads to large conformational strain increase and protein-protein interaction energies. Acidic residues are involved in the conformational change causing a succession of hydrogen bonds with TRP187. The pathway involves more than 300 dihedral angle transitions and helix unwinding.

The rotation of a water molecule buried inside a protein bovine pancreatic trypsin inhibitor (BPTI) was examined. Reaction path calculations using conjugate peak refinement were employed to compute the transition state and activation energy for the rotation in both BPTI and ice. The behavior of the structural water, which results to the interchange of two water hydrogens, was found to be similar in both ice and BPTI. The complex process involves two successive rotations around the orthogonal axes.

CHARMM force field technique helps study the preferred conformation and conformation interconversion pathways of a metacyclophane and two calix(4)arenes, 1 and 2. NMR data confirm the obtained relative stability of the conformers of the compounds. Conjugate peak refinement algorithm reveals the absence of preference for the 1,2Alt conformer or the 1,3Alt conformer intermediates during cone inversion. The cone to inverted-cone conversion of 1 is stepwise and produces a 1,2Alt conformer as intermediate. Two-dimensional NMR helps study the kinetics of various conversions.

Molecular mechanics calculations on the cis-trans imide isomerization of the proline dipeptide reveal the involvement of the proline backbone torsion angle, the pyramidalization of the imide nitrogen and the imide bond torsion angle in the isomerization process. Isomerization are better explained by the dihedral angle than by the torsion angle. Ab initio studies reveal the significant influence of torsion angle on the activation barrier. Interactions at zero torsional angle reduce the activation barrier and this autocatalytic transition state stabilization is vital for catalytic pathway in rotamases.

A molecular framework derived from the known structure of the FK506 binding protein (FKBP) complex underscores the pathway involved in rotamase enzyme FKBP-effected catalysis of prolyl isomerization. The substrate for the enzyme can bind in the form of type VIa proline turn with an intrasubstrate hydrogen bond between the N-H of phenyl and the C double bond O of the N-actyl group at the amino terminal of the enzyme. This hydrogen is bound stabilizes the enzyme-substrate complex.

The catalytic mechanism of backbone phosphodiester hydrolysis by the restriction enzyme EcoRV is examined by using hybrid quantum mechanical/molecular mechanical calculations. The protein environment is tuned to electrostatically stabilize the transition state structures and the direct catalytic impact of essential residues is analyzed.

A geometry model is developed to describe the orientation of ligand frgments around the nickel(II) center that influence the polymer microstructure. Preliminary investigations on material density and mechanical behavior by uniaxial stretching until failure point toward new material properties that can result from the simple ethylene monomer by catalyst design.

Quantum mechanical/molecular mechanical (QM/MM) reaction-path calculations were used for examining the protein photocycle. The barrier for the thermal cis-trans back-isomerization is lowered by retinal twisting and the rate-limiting barrier for back-isomerization is 5-6 kcal/mol larger than the barrier for the first proton-transfer step.

The Poisson-Boltzman/surface area PB/SA combined with a quantum mechanical description of the ligand in protein/ligand binding affinity calculation is investigated. The result reveals quantum mechanics/molecular mechanics QM/MM is promising new avenue for automated docking and scoring of flexible ligands.

The synthesis of a novel class of tricyclic pyrroles is accomplished by using a Pauson-Khand/Stetter/Paal-Knorr reaction sequence. The study of this reaction led to the discovery of an unprecedented substituent effect on the diastereoselectivity of the Mo(Co)6 mediated allenic Pauson-Khand reaction.

The proton transfer energy profiles in bacteriorhodopsin for various retinal isomeric states are investigated by employing quantum mechanics (QM)/ molecular mechanics (MM) minimum-energy path calculations. The proton transfer energy profiles are determined by two opposite-sign contributions, first the interaction between Asp85 and the 13-cis retinal, strongly favoring proton transfer, and the other arising from the protein electrostatic environment that stabilizes the ion pair state and gives rise to a proton transfer barrier.

The vibrational entropy change on the burial of a crystallographically well-ordered water molecule in bovine pancreatic trypsin inhibitor (BPTI) using normal-mode analysis is dissected. A detailed analysis is performed of how the translational and rotational degrees of freedom of the isolated water molecule are transformed into vibrational modes in the complex.

We demonstrate a facile method to improve upconversion quantum yields in Yb,Er-based nanoparticles via emission dye-sensitization. Using the commercially available dye ATTO 542, chosen for its high radiative rate and significant spectral overlap with the green emission of Er3+, we decorate the surfaces of sub-25 nm hexagonal-phase Na(Y/Gd/Lu)0.8F4:Yb0.18Er0.02 upconverting nanoparticles with varying dye concentrations. Upconversion photoluminescence and absorption spectroscopy provide experimental confirmation of energy transfer to and emission from the dye molecules. Upconversion quantum yield is observed to increase with dye sensitization, with the highest enhancement measured for the smallest particles investigated (10.9 nm in diameter); specifically, these dye-decorated particles are more than 2× brighter than are unmodified, organic-soluble nanoparticles and more than 10× brighter than are water-soluble nanoparticles. We also observe 3× lifetime reductions with dye adsorption, confirming the quantum yield enhancement to result from the high radiative rate of the dye. The approach detailed in this work is widely implementable, renders the nanoparticles water-soluble, and most significantly improves sub-15 nm nanoparticles, making our method especially attractive for biological imaging applications. [ABSTRACT FROM AUTHOR]

Lanthanide-doped nanocrystals are of particular interest for the research community not only due to their ability to shape light by downshifting, quantum cutting, and upconversion but also because novel optical properties can be found by the precise engineering of core-shell nanocrystals. Because of the large surface area-to-volume ratio of nanocrystals, the luminescence is typically suppressed by surface quenching. Here, we demonstrate a mechanism that exploits surface quenching processes to improve the luminescence of our core-shell lanthanide-doped nanocrystals. By carefully tuning the shell thickness of inert β-NaLuF4 around β-NaYF4 nanocrystals doped with Yb3+ and Er3+, we unravel the relationship between quantum yield and shell thickness, and quantify surface quenching rates for the relevant Er3+ and Yb3+ energy levels. This enhanced understanding of the system's dynamics allowed us to design nanocrystals with a surface quenching-assisted mechanism for bright NIR to NIR downshifting with a distinctive efficiency peak for an optimized shell thickness. [ABSTRACT FROM AUTHOR]

Scaffolded DNA origami nanostructures enable the self-assembly of arbitrarily shaped objects with unprecedented accuracy. Yet, varying physiological conditions are prone to induce slight structural changes in the nanoscale architecture. Here, we report on high precision measurements of overall shape and interhelical distance of three prototypic DNA origami structures in solution using synchrotron small-angle X-ray scattering. Sheet-, brick-, and cylinder-shaped DNA constructs were assembled and the shape factors determined with angstrom resolution from fits to the scattering profiles. With decreasing MgCl2 concentration electrostatic swelling of both shape cross section and interhelical DNA spacing of the DNA origami structures is observed. The structures tolerate up to 10% interhelical expansion before they disintegrate. In contrast, with increasing temperature, the cylinder-shaped structures show no thermal expansion in a wide temperature window before they abruptly melt above 50 °C. Details on molecular structure of DNA origami can also be obtained using in-house X-ray scattering equipment and, hence, allow for routine folding and stability testing of DNA-based agents that are designed to operate under varying salt conditions. [ABSTRACT FROM AUTHOR]

Upconversion (UC) is a promisingoption to enhance the efficiencyof solar cells by conversion of sub-bandgap infrared photons to higherenergy photons that can be utilized by the solar cell. The UC quantumyield is a key parameter for a successful application. Here the UCluminescence properties of Er3+-doped Gd2O2S are investigated by means of luminescence spectroscopy,quantum yield measurements, and excited state dynamics experiments.Excitation into the maximum of the 4I15/2→ 4I13/2Er3+absorption band around 1500nm induces very efficient UC emission from different Er3+excited states with energies above the silicon bandgap, in particular,the emission originating from the 4I11/2statearound 1000 nm. Concentration dependent studies reveal that the highestUC quantum yield is realized for a 10% Er3+-doping concentration.The UC luminescence is compared to the well-known Er3+-dopedβ-NaYF4UC material for which the highest UC quantumyield has been reported for 25% Er3+. The UC internal quantumyields were measured in this work for Gd2O2S:10%Er3+and β-NaYF4: 25%Er3+to be 12 ± 1% and 8.9 ± 0.7%, respectively, under monochromaticexcitation around 1500 nm at a power of 700 W/m2. The UCquantum yield reported here for Gd2O2S: 10%Er3+is the highest value achieved so far under monochromaticexcitation into the 4I13/2Er3+level.Power dependence and lifetime measurements were performed to understandthe mechanisms responsible for the efficient UC luminescence. We showthat the main process yielding 4I11/2UC emissionis energy transfer UC. [ABSTRACT FROM AUTHOR]

p38α mitogen-activated protein (MAP) kinase isa main targetin drug research concerning inflammatory diseases. Nevertheless, noinhibitor of p38α MAP kinase has been introduced to the market.This might be attributed to the fact that there is no inhibitor whichcombines outstanding activity in biological systems and selectivity.Herein an approach to the development of such inhibitors on the basisof the highly selective molecular probe Skepinone-L is described.Introduction of a “deep pocket” moiety addressing theDFG motif led to an increased activity of the compounds. Hydrophilicmoieties, addressing the solvent-exposed area adjacent to hydrophilicregion II, conserved a high activity of the compounds in a whole bloodassay. Combined with their outstanding selectivity and low ATP competitiveness,these inhibitors are very interesting candidates for use in biologicalsystems and in therapy. [ABSTRACT FROM AUTHOR]

Synthesis, biological testing, structure–activityrelationships(SARs), and selectivity of novel disubstituted dibenzosuberone derivativesas p38 MAP kinase inhibitors are described. Hydrophilic moieties wereintroduced at the 7-, 8-, and 9-position of the 2-phenylamino-dibenzosuberones,improving physicochemical properties as well as potency. Extremelypotent inhibitors were obtained, with half-maximal inhibitory concentration(IC50) values in the low nM range in a whole blood assaymeasuring the inhibition of cytokine release. The high potency ofthe target compounds together with the outstanding selectivity ofthis novel class of compounds toward p38 mitogen activated protein(MAP) kinase as compared to other kinases indicate them to be mostapplicable as tools in pharmacological research and eventually theymay foster a new generation of anti-inflammatory drugs. [ABSTRACT FROM AUTHOR]

Small-angle X-ray scattering data of melt-drawn high-density polyethylene (HDPE) have been analyzed by direct model fitting to projections on the drawing direction. On the basis of the assumption of an infinite paracrystalline lattice as proposed by Hosemann and a rectangular density profile, several additional assumptions have been tested. It turned out that to achieve good fits we have to introduce a finiteness of the lattice for the used samples. Transition zones between crystalline and amorphous regions also improve the model but are of less importance. The most suitable model has been tested on data from an annealing and subsequent cooling process. We show that the additional parameters gained in the modeling approach compared to peak analysis or correlation function analysis lead to a better understanding of the structures and processes in the samples. [ABSTRACT FROM AUTHOR]

The first proton transport step following photon absorption in bacteriorhodopsin is from the 13-cis retinal Schiff base to Asp85. Configurational and energetic determinants of this step are investigated here by performing quantum mechanical/molecular mechanical minimum-energy reaction-path calculations. The results suggest that retinal can pump protons when in the 13-cis, 15-anti conformation but not when 13-cis, 15-syn. Decomposition of the proton transfer energy profiles for various possible pathways reveals a conflict between the effect of the intrinsic proton affinities of the Schiff base and Asp85, which favors the neutral, product state (i.e., with Asp85 protonated), with the mainly electrostatic interaction between the protein environment with the reacting partners, which favors the ion pair reactant state (i.e., with retinal protonated). The rate-limiting proton-transfer barrier depends both on the relative orientations of the proton donor and acceptor groups and on the pathway followed by the proton; depending on these factors, the barrier may arise from breaking and forming of hydrogen bonds involving the Schiff base, Asp85, Asp212, and water w402, and from nonbonded interactions involving protein groups that respond to the charge rearrangements in the Schiff base region. [ABSTRACT FROM AUTHOR]

Examines the annexin V transition using conjugate peak refinement. Conformational change accompanying the binding of calcium to domain III; Force field and solvent shielding; Conformational transition in end state structures; Calculation of the transition path.

Enantiopure ( P ) 4 - and ( M ) 4 -configured alleno-acetylenic cage (AAC) receptors offer a highly defined interior for the complexation and structure elucidation of small molecule fragments of the stereochemically complex chlorosulfolipid danicalipin A. Solution (NMR), solid state (X-ray), and theoretical investigations of the formed host-guest complexes provide insight into the conformational preferences of 14 achiral and chiral derivatives of the danicalipin A chlorohydrin core in a confined, mostly hydrophobic environment, extending previously reported studies in polar solvents. The conserved binding mode of the guests permits deciphering the effect of functional group replacements on Gibbs binding energies Δ G . A strong contribution of conformational energies toward the binding affinities is revealed, which explains why the denser packing of larger apolar domains of the guests does not necessarily lead to higher association. Enantioselective binding of chiral guests, with energetic differences ΔΔ G 293 K up to 0.7 kcal mol -1 between diastereoisomeric complexes, is explained by hydrogen- and halogen-bonding, as well as dispersion interactions. Calorimetric studies (ITC) show that the stronger binding of one enantiomer is accompanied by an increased gain in enthalpy Δ H but at the cost of a larger entropic penalty T Δ S stemming from tighter binding.

We synthesized and characterized a set of ultrasmall hexagonal-phase NaGdF 4 : 20% Yb 3+ , 2% Er 3+ upconversion nanoparticles with core diameters of 3.7 ± 0.5 nm. In order to assess passivation effects and the influence of possible core-shell intermixing and to identify optimum particle structures for combined imaging in the visible and near-infrared (vis-NIR: 410-850 nm) and short-wave infrared (SWIR: 1520 nm), NaYF 4 shells of varying thicknesses (monolayer to 10 nm) were introduced and the influence of this parameter on the upconversion and downshifting photoluminescence of these particles was studied at different excitation power densities. This included excitation power-dependent emission spectra, slope factors, quantum yields, and excited state decay kinetics. These measurements revealed enhancement factors of the upconversion quantum yield of >10 000 in the low power region and an excitation power density-independent quantum yield of the downshifted emission at 1520 nm between 0.1 and 14%. The optimized shell thickness for combined vis and SWIR imaging was identified as 5 nm. Moreover, lifetimes and quantum yields can be continuously tuned by shell thickness which can be exploited for lifetime multiplexing and encoding. The fact that we did not observe a saturation of the upconversion quantum yield or the excited state decay kinetics with increasing shell thickness is ascribed to a strong intermixing of the active core with the inert shell during the shelling procedure. This indicates the potential of spectroscopic tools to detect cation intermixing.

Precise morphology and composition control is vital for designing multifunctional lanthanide-doped core/shell nanocrystals. Herein, we report controlled isotropic and anisotropic shell growth techniques in hexagonal sodium rare-earth tetrafluoride (β-NaLnF 4 ) nanocrystals by exploiting the kinetics of the shell growth. A drastic change of the shell morphology was observed by changing the injection rate of the shell precursors while keeping all other reaction conditions constant. We obtained isotropic shell growth for fast sequential injection and a preferred growth of the shell layers along the crystal's c-axis [001] for slow dropwise injection. Using this slow shell growth technique, we have grown rod-like shells around different almost spherical core nanocrystals. Bright and efficient upconversion was measured for both isotropic and rod-like shells around β-NaYF 4 nanocrystals doped with Yb 3+ /Er 3+ and Yb 3+ /Tm 3+ . Photoluminescence upconversion quantum yield and lifetime measurements reveal the high quality of the core/shell nanocrystal. Furthermore, multishell rod-like nanostructures have been prepared with optically active cores and tips separated by an inert intermediate shell layer. The controlled anisotropic shell growth allows the design of new core/multishell nanostructures and enables independent investigations of the chemistry and physics of different nanocrystal facets.

Lead halide perovskites hold promise for photonic devices, due to their superior optoelectronic properties. However, their use is limited by poor stability and toxicity. We demonstrate enhanced water and light stability of high-surface-area colloidal perovskite nanocrystals by encapsulation of colloidal CsPbBr 3 quantum dots into matched hydrophobic macroscale polymeric matrices. This is achieved by mixing the quantum dots with presynthesized high-molecular-weight polymers. We monitor the photoluminescence quantum yield of the perovskite-polymer nanocomposite films under water-soaking for the first time, finding no change even after >4 months of continuous immersion in water. Furthermore, photostability is greatly enhanced in the macroscale polymer-encapsulated nanocrystal perovskites, which sustain >10 10 absorption events per quantum dot prior to photodegradation, a significant threshold for potential device use. Control of the quantum dot shape in these thin-film polymer composite enables color tunability via strong quantum-confinement in nanoplates and significant room temperature polarized emission from perovskite nanowires. Not only does the high-molecular-weight polymer protect the perovskites from the environment but also no escaped lead was detected in water that was in contact with the encapsulated perovskites for months. Our ligand-passivated perovskite-macroscale polymer composites provide a robust platform for diverse photonic applications.

Organometal halide perovskites have recently emerged displaying a huge potential for not only photovoltaic, but also light emitting applications. Exploiting the optical properties of specifically tailored perovskite nanocrystals could greatly enhance the efficiency and functionality of applications based on this material. In this study, we investigate the quantum size effect in colloidal organometal halide perovskite nanoplatelets. By tuning the ratio of the organic cations used, we can control the thickness and consequently the photoluminescence emission of the platelets. Quantum mechanical calculations match well with the experimental values. We find that not only do the properties of the perovskite, but also those of the organic ligands play an important role. Stacking of nanoplatelets leads to the formation of minibands, further shifting the bandgap energies. In addition, we find a large exciton binding energy of up to several hundreds of meV for nanoplatelets thinner than three unit cells, partially counteracting the blueshift induced by quantum confinement. Understanding of the quantum size effects in perovskite nanoplatelets and the ability to tune them provide an additional method with which to manipulate the optical properties of organometal halide perovskites.

An efficient synthesis of 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2, 1) is reported. The route described allows for diversification of the parent structure to prepare seven analogues of 1 in which the positioning of electrophilic sites is varied. These analogues were tested in SAR studies for their ability to reduce the secretion of proinflammatory cytokines. It was shown that the endocyclic enone is crucial for the bioactivity investigated and that the conjugated ω-side chain serves in a reinforcing manner.

Relaxation of the twisted-retinal photoproduct state triggers proton-coupled reaction cycle in retinal proteins. Given the crowded protein environments in which the retinal resides, a key open question is whether the retinal relaxation path is governed by the intrinsic torsional properties of the retinal or rather by the interactions of the retinal with protein and water groups. Here we address this question by performing systematic quantum mechanical/molecular mechanical molecular dynamics computations of retinal dynamics in bacteriorhodopsin at different temperatures, reaction path computations, and assessment of the vibrational fingerprints of the retinal molecule. The results demonstrate a complex dependence of the retinal dynamics and preferred geometry on temperature. As the temperature increases, the retinal dihedral angle samples values largely determined by its internal conformational energy. The protein environment shapes the energetics of retinal relaxation and provides hydrogen-bonding partners that stabilize the retinal geometry.

Thermogravimetric analysis and a synchrotron small-angle X-ray scattering technique were employed to characterize the structural evolution of a polymeric latex dispersion during the first three stages of film formation at different temperatures and relative humidities. Three intermediate stages were identified: (1) stage I*, (2) stage I**, and (3) stage II*. Stage I* is intermediate to the conventionally defined stages I and II, where latex particles began to crystallization. The change of drying temperature affects the location of the onset of ordering, whereas relative humidity does not. Stage I** is where the latex particles with their diffuse shell of counterions in the fcc structure are in contact with each other. The overlapping of these layers results in an acceleration of the lattice shrinkage due to a decrease of effective charges. Stage II* is where the latex particles, dried well above their T(g), are deformed and packed only partially during film formation due to incomplete evaporation of water in the latex film. This is because of a rapid deformation of the soft latex particles at the liquid/air interface so that a certain amount of water is unable to evaporate from the latex film effectively. For a latex dispersion dried at a temperature close to its minimum film formation temperature, the transition between stages II and III can be continuous because the latex particles deform at a much slower rate, providing sufficient surface area for water evaporation.

Structural rearrangement in a latex powder during dry sintering at temperatures higher than the minimum film formation temperature was investigated by means of synchrotron small-angle X-ray scattering. Two major effects were identified: (1) Deformation of latex particles leads to a closure of voids between them and an extensive perfectioning of the face centered cubic colloidal crystalline ordering. Such an improvement of the colloidal crystalline structure involves preferential crystal growth along certain crystallographic directions as was evidenced by the measured unmatched relative diffraction intensity distribution of the crystallographic (111) and (220) planes. (2) Interdiffusion of polymeric chains between adjacent particles promotes a nanometer sized aggregation of nonpolymeric materials previously located in the interstices between particles. Size and size distribution of the aggregates at different dry sintering conditions were evaluated by using a model considering spheres dispersed in the system., (© 2011 American Chemical Society)

AM1/d parameters are derived for magnesium, optimized for modeling reactions in metalloenzymes. The parameters are optimized with a Monte Carlo procedure so as to reproduce the geometries and energies of a training set calculated with density functional theory. The training set consists of compounds with magnesium coordinated to the oxygen atom of typical biological ligands. Optimization of AM1 parameters without extension to d functions leaves serious errors. The new AM1/d parameters provide a clear improvement in accuracy compared to the standard semiempirical methods AM1 and MNDO/d and will be particularly useful for modeling reactions in large biological systems at low computational cost.

Functionally relevant transitions between native conformations of a protein can be complex, involving, for example, the reorganization of parts of the backbone fold, and may occur via a multitude of pathways. Such transitions can be characterized by a transition network (TN), in which the experimentally determined end state structures are connected by a dense network of subtransitions via low-energy intermediates. We show here how the computation of a TN can be achieved for a complex protein transition. First, an efficient hierarchical procedure is used to uniformly sample the conformational subspace relevant to the transition. Then, the best path which connects the end states is determined as well as the rate-limiting ridge on the energy surface which separates them. Graph-theoretical algorithms permit this to be achived by computing the barriers of only a small number out of the many subtransitions in the TN. These barriers are computed using the Conjugate Peak Refinement method. The approach is illustrated on the conformational switch of Ras p21. The best and the 12 next-best transition pathways, having rate-limiting barriers within a range of 10 kcal/mol, were identified. Two main energy ridges, which respectively involve rearrangements of the switch I and switch II loops, show that switch I must rearrange by threading Tyr32 underneath the protein backbone before the rate-limiting switch II rearrangement can occur, while the details of the switch II rearrangement differ significantly among the low-energy pathways.