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Powder deaggregation in Dry Powder Inhalers (DPI) with carrier-based formulations is a key process for the effectiveness of drug administration. Carrier-wall collisions are one of the recognised mechanisms responsible for active pharmaceutical ingredient (API) aerosolisation, and DPI geometries are designed to maximise their efficacy. The detachment of fine and cohesive API particles is investigated at a fundamental level by simulating with DEM the normal collision of a carrier sphere with an API particle attached. The impact velocity at which detachment occurs (escape velocity) is determined as a function of key parameters, such as cohesiveness, coefficient of restitution, static and rolling friction. An analytical model for the escape velocity is then derived, examining the role of the initial position of the particle, cohesion model and particle size. Finally, the results are framed in the context of DPI inhalers, comparing the results obtained with impact velocities typically recorded in commercial devices. [ABSTRACT FROM AUTHOR]

We report on the properties of the (0001) covellites surfaces, which we investigate by periodic slab density functional theory calculations. The absolute surface energies have been computed for all bulk terminations, showing that surfaces terminated by the flat CuS layer are associated with the lowest surface energy. Cleavage is predicted to occur across the [0001] interlayer Cu-S bond. The surfaces obtained by lowest energy cleavage are analyzed in terms of the atomic vertical relaxation, workfunction, and surface band structure. Our study predicts the presence of a shallow pz-derived surface state located 0.26 eV below the Fermi level, which is set to play an important role in the surface reactivity of covellite. [ABSTRACT FROM AUTHOR]

Dynamical properties are of great importance in determining the behavior of synthetic and natural molecules, but capturing them by computational methods is a nontrivial task. Very often the time scales of the relevant phenomena are far beyond the typical time windows accessible by classical Molecular Dynamics (MD) simulations, currently limited to the order of microseconds on standard laboratory workstations. On the other hand, biased and accelerated simulations allow for fast and thorough exploration of the molecular conformational space, but they lose the dynamic information. The problem of recovering dynamics from biased/accelerated simulations is a very active field of research, but no totally robust/reliable solutions have been given yet. In this paper it is shown how the Smoluchowski equation, in the framework of Diffusion Theory (DT), can be used to bridge this gap, and dynamical properties, in the form of time correlation functions (TCFs), can be extracted also from such kind of simulations. DT is first extended (EDT) to express the mobility tensors entering the Smoluchowski operator in terms of a recently introduced unified and regularized Rotne–Prager–Yamakawa approximation, [P. J. Zuk, E. Wajnryb, K. A. Mizerski, P. Szymczak, J. Fluid. Mech. 2014, 741, R5, 1–13] also involving mixed rotation‐translation contributions, and rotation‐rotation terms beside the classical translation‐translation ones, so far used in DT. Then, the method is applied to recover the dynamics of a nontrivial example of a peptide in explicit water from the first 200 ns of a Replica Exchange Molecular Dynamics simulation, which is a popular computational method that destroys the long time dynamics. EDT dynamics were found to favorably compare against those coming from a standard MD simulation of the same system, requiring a time window of 30 μs to converge. This result shows that EDT is a tool of practical value to recover the long time dynamics of systems in diffusive regimes from biased/accelerated simulations, to be exploited in those cases when direct evaluation by standard MD is unfeasible. [ABSTRACT FROM AUTHOR]

In this work a new method is proposed for the choice of basis functions in diffusion theory (DT) calculations. This method, named hybrid basis approach (HBA), combines the two previously adopted long time sorting procedure (LTSP) and maximum correlation approximation (MCA) techniques; the first emphasizing contributions from the long time dynamics, the latter being based on the local correlations along the chain. In order to fulfill this task, the HBA procedure employs a first order basis set corresponding to a high order MCA one and generates upper order approximations according to LTSP. A test of the method is made first on a melt of cis-1,4-polyisoprene decamers where HBA and LTSP are compared in terms of efficiency. Both convergence properties and numerical stability are improved by the use of the HBA basis set whose performance is evaluated on local dynamics, by computing the correlation times of selected bond vectors along the chain, and on global ones, through the eigenvalues of the diffusion operator L. Further use of the DT with a HBA basis set has been made on a 71-mer of syndiotactic trans-1,2-polypentadiene in toluene solution, whose dynamical properties have been computed with a high order calculation and compared to the “numerical experiment” provided by the molecular dynamics (MD) simulation in explicit solvent. The necessary equilibrium averages have been obtained by a vacuum trajectory of the chain where solvent effects on conformational properties have been reproduced with a proper screening of the nonbonded interactions, corresponding to a definite value of the mean radius of gyration of the polymer in vacuum. Results show a very good agreement between DT calculations and the MD numerical experiment. This suggests a further use of DT methods with the necessary input quantities obtained by the only knowledge of some experimental values, i.e., the mean radius of gyration of the chain and the viscosity of the solution, and by a suitable vacuum trajectory, with great savings in computational time required. This offers a theoretical bridge between the experimental static and dynamical properties of polymers. [ABSTRACT FROM AUTHOR]

Carbonic anhydrases (CAs, EC 4.2.1.1) are ubiquitous metalloenzymes, grouped into seven different classes, which catalyze the reaction of CO2 hydration to bicarbonate and protons. All of the fifteen human isoforms reported to date belong to the α-class and contain zinc as a cofactor. The structure of human Zn,Cu-CA II has been solved which contains a copper ion bound at its N-terminal, coordinated to His4 and His64. In the active site a dioxygen molecule is coordinated to the zinc ion. Since dioxygen is a rather unexpected CA ligand, molecular dynamics (MD) simulations were performed which suggested a superoxide character of the zinc bound O2. [ABSTRACT FROM AUTHOR]

The quest for materials with metal-like properties as alternatives to noble metals is an intense area of research that is set to lead to dramatic improvements in technologies based on plasmonics. Here, we present intermediate band (IB) semiconductor nanocrystals (NCs) as a class of all-dielectric nanomaterials providing quasi-static optical resonances. We show that IB NCs can display a negative permittivity in a broad range of visible wavelengths, enabling a metal-like optical response despite the absence of free carriers in the NC ground state. Using a combination of spectroscopy measurements and ab initio calculations, we hereby provide a theoretical model for both the linear and nonlinear optical properties of chalcopyrite CuFeS2 NCs, as a case study of IB semiconductor nanomaterials. Our results rationalize the high performance of IB nanomaterials as photothermal agents and suggest the use of IB semiconductors as alternatives to noble metals for technologies based on plasmonic materials. [ABSTRACT FROM AUTHOR]

Wasserstoffatome sind entscheidend bei der Vermittlung von Protein ‐ Ligand ‐ Wechselwirkungen. Sie bestimmen die Qualität entstehender H ‐ Brückennetzwerke und definieren Protonierungszustände gebundener Liganden. Die strukturelle Visualisierung von H ‐ Atomen ist röntgenkristallographisch nur selten möglich. Hier wurden die Wasserstoffpositionen von Anilin und 2 ‐ Aminopyridin im an die Serinprotease Trypsin gebundenen Zustand durch Neutronenbeugung untersucht. Die resultierenden Strukturen wurden mit der höchsten bisher für Proteine mit >100 Aminosäuren erzielten Auflösung erhalten. Dies ermöglicht die exakte Beschreibung der Protonierungszustände und Wechselwirkungen mit umgebenden Wassermolekülen. Trotz seines niedrigen pKa ‐ Werts von 4.6 und einem Abstand von 3.6 Å zum geladenen Asp189 am Boden der S1 ‐ Tasche liegt die Aminogruppe von Anilin protoniert vor. Hingegen wird in 2 ‐ Aminopyridin das Pyridin ‐ N ‐ Atom protoniert, obwohl dessen Aminogruppe um 1.6 Å näher an Asp189 liegt. Folglich ist, abgesehen von Ladungs ‐ Ladungs ‐ Abständen, die Stabilität der möglichen Tautomere ausschlaggebend für den erhaltenen Bindungsmodus und damit entscheidend für die Vorhersage von Bindungsmodi. Wo sind die Protonen? H ‐ Atome sind experimentell meist schwierig zu visualisieren, sind aber der Schlüssel für das Verständnis der Protein ‐ Ligand ‐ Erkennung. Neutronenkristallographie zufolge nimmt die Aminogruppe von Anilin trotz ihres niedrigen pKa ‐ Wertes ein Proton bei der Bindung an die archetypische Serinprotease Trypsin auf. Dagegen wird 2 ‐ Aminopyridin am Pyridin ‐ Stickstoffatom protoniert, was zum stabileren Tautomer dieses Moleküls führt. [ABSTRACT FROM AUTHOR]

Hydrogen atoms play a key role in protein-ligand recognition. They determine the quality of established H-bonding networks and define the protonation of bound ligands. Structural visualization of H atoms by X-ray crystallography is rarely possible. We used neutron diffraction to determine the positions of the hydrogen atoms in the ligands aniline and 2-aminopyridine bound to the archetypical serine protease trypsin. The resulting structures show the best resolution so far achieved for proteins larger than 100 residues and allow an accurate description of the protonation states and interactions with nearby water molecules. Despite its low p Ka of 4.6 and a large distance of 3.6 Å to the charged Asp189 at the bottom of the S1 pocket, the amino group of aniline becomes protonated, whereas in 2-aminopyridine, the pyridine nitrogen picks up the proton although its amino group is 1.6 Å closer to Asp189. Therefore, apart from charge-charge distances, tautomer stability is decisive for the resulting binding poses, an aspect that is pivotal for predicting correct binding. [ABSTRACT FROM AUTHOR]

The structural and compositional stabilities of two-dimensional (2D) Bi2Te3 and Bi2Se3 nanocrystals, produced by both colloidal synthesis and by liquid phase exfoliation, were studied by in situ transmission electron microscopy (TEM) during annealing at temperatures between 350 and 500 °C. The sublimation process induced by annealing is structurally and chemically anisotropic and takes place through the preferential dismantling of the prismatic {011̅0} type planes, and through the preferential sublimation of Te (or Se). The observed anisotropic sublimation is independent of the method of nanocrystal's synthesis, their morphology, or the presence of surfactant molecules on the nanocrystals surface. A thickness-dependent depression in the sublimation point has been observed with nanocrystals thinner than about 15 nm. The Bi2Se3 nanocrystals were found to sublimate below 280 °C, while the Bi2Te3 ones sublimated at temperatures between 350 and 450 °C, depending on their thickness, under the vacuum conditions in the TEM column. Density functional theory calculations confirm that the sublimation of the prismatic {011̅0} facets is more energetically favorable. Within the level of modeling employed, the sublimation occurs at a rate about 700 times faster than the sublimation of the {0001} planes at the annealing temperatures used in this work. This supports the distinctly anisotropic mechanisms of both sublimation and growth of Bi2Te3 and Bi2Se3 nanocrystals, known to preferentially adopt a 2D morphology. The anisotropic sublimation behavior is in agreement with the intrinsic anisotropy in the surface free energy brought about by the crystal structure of Bi2Te3 or Bi2Se3. [ABSTRACT FROM AUTHOR]

The binding of sulfonamides to human carbonic anhydrase II (hCAII) is a complex and long-debated example of protein-ligand recognition and interaction. In this study, we investigate the para-substituted n-alkyl and hydroxyethylene-benzenesulfonamides, providing a complete reconstruction of their binding pathway to hCAII by means of large-scale molecular dynamics simulations, density functional calculations, surface plasmon resonance (SPR) measurements, and X-ray crystallography experiments. Our analysis shows that the protein-ligand association rate (kon) dramatically increases with the ligand's hydrophobicity, pointing to the existence of a prebinding stage largely stabilized by a favorable packing of the ligand's apolar moieties with the hCAII "hydrophobic wall". The characterization of the binding pathway allows an unprecedented understanding of the structure-kinetic relationship in hCAII/benzenesulfonamide complexes, depicting a paradigmatic scenario for the multistep binding process in protein-ligand systems. [ABSTRACT FROM AUTHOR]

Synthesisapproaches to colloidal Cu3P nanocrystals (NCs) have beenrecently developed, and their optical absorption features in the near-infrared(NIR) have been interpreted as arising from a localized surface plasmonresonance (LSPR). Our pump–probe measurements on platelet-shapedCu3-xP NCs corroborate the plasmoniccharacter of this absorption. In accordance with studies on crystalstructure analysis of Cu3P dating back to the 1970s, ourdensity functional calculations indicate that this material is substoichiometricin copper, since the energy of formation of Cu vacancies in certaincrystallographic sites is negative, that is, they are thermodynamicallyfavored. Also, thermoelectric measurements point to a p-type behaviorof the majority carriers from films of Cu3-xP NCs. It is likely that both the LSPR and the p-type characterof our Cu3-xP NCs arise from thepresence of a large number of Cu vacancies in such NCs. Motivatedby the presence of Cu vacancies that facilitate the ion diffusion,we have additionally exploited Cu3-xP NCs as a starting material on which to probe cation exchange reactions.We demonstrate here that Cu3-xPNCs can be easily cation-exchanged to hexagonal wurtzite InP NCs,with preservation of the anion framework (the anion framework in Cu3-xP is very close to that of wurtziteInP). Intermediate steps in this reaction are represented by Cu3-xP/InP heterostructures, as a consequenceof the fact that the exchange between Cu+and In3+ions starts from the peripheral corners of each NC and graduallyevolves toward the center. The feasibility of this transformationmakes Cu3-xP NCs an interestingmaterial platform from which to access other metal phosphides by cationexchange. [ABSTRACT FROM AUTHOR]

High-angle annular dark-field scanning transmission electron microscopy (HAADF STEM) has been performed along the low-index zone axes of the o-Al4(Cr,Fe) complex metallic alloy to obtain a real-space representation of the crystal structure and to elucidate the material's inherent structural disorder. By comparing experiments with multislice STEM simulations, the model previously suggested by X-ray diffraction is further refined to provide a new set of positions and occupancies for the transition metal atoms. Pmnb is suggested as the new space group for the o-Al4(Cr,Fe) phase. A nonperiodic layer-type modulation, averaged out in bulk diffraction methods, is detected, corroborating the need for complementing bulk diffraction analysis with real-space imaging to derive the true crystal structure of Al4(Cr,Fe). [ABSTRACT FROM AUTHOR]

Hydrogen bonds are key interactions determining protein-ligand binding affinity and therefore fundamental to any biological process. Unfortunately, explicit structural information about hydrogen positions and thus H-bonds in protein-ligand complexes is extremely rare and similarly the important role of water during binding remains poorly understood. Here, we report on neutron structures of trypsin determined at very high resolutions ≤1.5 Å in uncomplexed and inhibited state complemented by X-ray and thermodynamic data and computer simulations. Our structures show the precise geometry of H-bonds between protein and the inhibitors N-amidinopiperidine and benzamidine along with the dynamics of the residual solvation pattern. Prior to binding, the ligand-free binding pocket is occupied by water molecules characterized by a paucity of H-bonds and high mobility resulting in an imperfect hydration of the critical residue Asp189. This phenomenon likely constitutes a key factor fueling ligand binding via water displacement and helps improving our current view on water influencing protein-ligand recognition. Trypsin is a serine protease. Here the authors present the high resolution X-ray and neutron diffraction structures of uncomplexed and inhibitor bound trypsin that provide insights into the geometry of H-bonds in the active site of the enzyme and molecular dynamics simulations reveal the kinetics of ligand binding induced desolvation. [ABSTRACT FROM AUTHOR]

Drug discovery is expensive and high-risk. Its main reasons of failure are lack of efficacy and toxicity of a drug candidate. Binding affinity for the biological target has been usually considered one of the most relevant figures of merit to judge a drug candidate along with bioavailability, selectivity and metabolic properties, which could depend on off-target interactions. Nevertheless, affinity does not always satisfactorily correlate with in vivo drug efficacy. It is indeed becoming increasingly evident that the time a drug spends in contact with its target (aka residence time) can be a more reliable figure of merit. Experimental kinetic measurements are operatively limited by the cost and the time needed to synthesize compounds to be tested, to express and purify the target, and to setup the assays. We present here a simple and efficient molecular-dynamics-based computational approach to prioritize compounds according to their residence time. We devised a multiple-replica scaled molecular dynamics protocol with suitably defined harmonic restraints to accelerate the unbinding events while preserving the native fold. Ligands are ranked according to the mean observed scaled unbinding time. The approach, trivially parallel and easily implementable, was validated against experimental information available on biological systems of pharmacological relevance. [ABSTRACT FROM AUTHOR]

We investigated pseudo-cubic Cu 2- x Te nanosheets using electron diffraction tomography and high-resolution HAADF-STEM imaging. The structure of this metastable nanomaterial, which has a strong localized surface plasmon resonance in the near-infrared region, was determined ab initio by 3D electron diffraction data recorded in low-dose nanobeam precession mode, using a new generation background-free single-electron detector. The presence of two different, crystallographically defined modulations creates a 3D connected vacancy channel system, which may account for the strong plasmonic response of this material. Moreover, a pervasive rotational twinning is observed for nanosheets as thin as 40 nm, resulting in a tetragonal pseudo-symmetry.

Herein, we present a new computational approach for analyzing hydration patterns in biomolecular systems. This protocol aims to efficiently identify regions where structural waters may be located and, in the case of protein-ligand binding, where displacing one or more water molecules could be advantageous in terms of affinity and/or residence time. We validated our approach on the adenosine A 2A receptor, a target of significant pharmaceutical relevance. The results of the approach are enriched with an extensive analysis of hydration in A 2A and other members of the A-family of GPCRs using available crystallographic evidence and reviewing existing literature. As per the protein-ligand complex case, we conducted a more detailed study of a series of triazine analogues inhibiting A 2A . The proposed approach provides results in good agreement with existing data and offers interpretability and simple and fast applicability.

A number of structural factors modulate the activity of Abelson (Abl) tyrosine kinase, whose deregulation is often related to oncogenic processes. First, only the open conformation of the Abl kinase domain's activation loop (A-loop) favors ATP binding to the catalytic cleft. In this regard, the trans-autophosphorylation of the Y412 residue, which is located along the A-loop, favors the stability of the open conformation, in turn enhancing Abl activity. Another key factor for full Abl activity is the formation of active conformations of the catalytic DFG motif in the Abl kinase domain. Furthermore, binding of the SH2 domain to the N-lobe of the Abl kinase was recently demonstrated to have a long-range allosteric effect on the stabilization of the A-loop open state. Intriguingly, these distinct structural factors imply a complex signal transmission network for controlling the A-loop's flexibility and conformational preference for optimal Abl function. However, the exact dynamical features of this signal transmission network structure remain unclear. Here, we report on microsecond-long molecular dynamics coupled with enhanced sampling simulations of multiple Abl model systems, in the presence or absence of the SH2 domain and with the DFG motif flipped in two ways (in or out conformation). Through comparative analysis, our simulations augment the interpretation of the existing Abl experimental data, revealing a dynamical network of interactions that interconnect SH2 domain binding with A-loop plasticity and Y412 autophosphorylation in Abl. This signaling network engages the DFG motif and, importantly, other conserved structural elements of the kinase domain, namely, the EPK-ELK H-bond network and the HRD motif. Our results show that the signal propagation for modulating the A-loop spatial localization is highly dependent on the HRD motif conformation, which thus acts as the central hub of this (allosteric) signaling network controlling Abl activation and function.

The ability of amphiphilic polymers to self-assemble and form a gel or gel-like layer has been investigated by means of both experimental and theoretical studies on alkylated derivatives of poly(acrylic acid). Experiments were performed to determine the relationship between amphiphilic polymer chemistry, structure, water retention, and friction in the presence of hydrophobic substrates. The results indicate that the amphiphilic polymer forms a water-enriched, friction-reducing adsorbed layer on hydrophobic surfaces. The shear moduli and viscosities of the adsorbed layers, as determined by fitting the Voigt model to QCM-D data, were consistent with the presence of a gel. Computational studies on HPAA-12 were performed and are consistent with the presence of adsorbed conformations, in which the lowest free energy in the model corresponded to a partially adsorbed molecule, with a small fraction of hydrophobic side chains being compelled, for configurational reasons, to point into the bulk water. This would support the possibility of the formation of either a gel-like layer or surface aggregation. However, because the adsorption experiments showed no evidence of aggregation, this strongly suggests the formation of a gel.

Scratching the surface: Formation of a monolayer of 2H-tetraphenylporphyrins (2H-TPP) on Ag(111), either by sublimation of a multilayer in the range 525-600 K or by annealing (at the same temperature) a monolayer deposited at room temperature, induces a chemical modification of the molecules. Rotation of the phenyl rings into a flat conformation is observed and tentatively explained, by using DFT calculations, as a peculiar reaction due to molecular dehydrogenation., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)