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Recent studies show that curcumin, a naturally fluorescent dye, can be used for the noninvasive optical imaging of retinal amyloid-β (Aβ) plaques. We investigated the molecular basis for curcumin's specificity for hierarchical Aβ structures using molecular dynamics simulations, with a focus on how curcumin is able to detect and discriminate different amyloid morphologies. Curcumin inhibits and breaks up β-sheet formation in Aβ monomers. With disordered Aβ structures, curcumin forms a coarse-grained composite structure. With an ordered fibril, curcumin's interaction is highly specific, and the curcumin molecules are deposited in the fibril groove. Curcumin tends to self-aggregate, which is finely balanced with its affinity for Aβ. This tendency concentrates curcumin molecules at Aβ deposition sites, potentially increasing the fluorescence signal. This is probably why curcumin is such an effective amyloid imaging agent.

Force fields form the basis for classical molecular simulations and their accuracy is crucial for the quality of, for instance, protein-ligand binding simulations in drug discovery. The huge diversity of small molecule chemistry makes it a challenge to build and parameterize a suitable force field. The Open Force Field Initiative is a combined industry and academic consortium developing a state-of-the-art small molecule force field. In this report industry members of the consortium worked together to objectively evaluate the performance of the force fields (referred to here as OpenFF) produced by the initiative on a combined public and proprietary dataset of 19,653 relevant molecules selected from their internal research and compound collections. This evaluation was important because it was completely blind; at most partners, none of the molecules or data were used in force field development or testing prior to this work. We compare the Open Force Field "Sage" version 2.0.0 and "Parsley" version 1.3.0 with GAFF-2.11-AM1BCC, OPLS4 and SMIRNOFF99Frosst. We analyzed force field-optimized geometries and conformer energies compared to reference quantum mechanical data. We show that OPLS4 performs best, and the latest Open Force Field release shows a clear improvement compared to its predecessors. The performance of established force fields such as GAFF-2.11 was generally worse. While OpenFF researchers were involved in building the benchmarking infrastructure used in this work, benchmarking was done entirely in-house within industrial organizations and the resulting assessment is reported here. This work assesses the force field performance using separate benchmarking steps, external datasets, and involving external research groups. This effort may also be unique in terms of the number of different industrial partners involved, with 10 different companies participating in the benchmark efforts.

The development of accurate transferable force fields is key to realizing the full potential of atomistic modelling in the study of biological processes such as protein--ligand binding for drug discovery. State-of-the-art transferable force fields, such as those produced by the Open Force Field Initiative, use modern software engineering and automation techniques to progressively yield accuracy improvements. However, force field torsion parameters, which must effectively account for many stereoelectronic and steric effects, are generally considered to be less transferable than other force field parameters and are therefore often targets for bespoke parametrization. Here, we present the Open Force Field QCSubmit and BespokeFit software packages that, when combined, facilitate the fitting of torsion parameters to quantum mechanical reference data at scale. We demonstrate the use of QCSubmit for simplifying the process of creating and archiving large numbers of quantum chemical calculations, by generating a dataset of 671 torsion scans for drug-like fragments. We use BespokeFit to derive individual torsion parameters for each of these molecules, thereby reducing the root mean squared error in the potential energy surface from 1.1 kcal/mol, using the original transferable force field, to 0.4 kcal/mol using the bespoke version. Furthermore, we employ the bespoke force fields to compute the relative binding free energies of a congeneric series of inhibitors of the TYK2 protein, and demonstrate further improvements in accuracy, compared to the base force field (MUE reduced from 0.56$^{0.77}_{0.39}$ to 0.42$^{0.59}_{0.28}$ kcal/mol and R$^2$ correlation improved from 0.72$^{0.87}_{0.35}$ to 0.93$^{0.97}_{0.84}$).

Community efforts in the computational molecular sciences (CMS) are evolving toward modular, open, and interoperable interfaces that work with existing community codes to provide more functionality and composability than could be achieved with a single program. The Quantum Chemistry Common Driver and Databases (QCDB) project provides such capability through an application programming interface (API) that facilitates interoperability across multiple quantum chemistry software packages. In tandem with the Molecular Sciences Software Institute and their Quantum Chemistry Archive ecosystem, the unique functionalities of several CMS programs are integrated, including CFOUR, GAMESS, NWChem, OpenMM, Psi4, Qcore, TeraChem, and Turbomole, to provide common computational functions, i.e., energy, gradient, and Hessian computations as well as molecular properties such as atomic charges and vibrational frequency analysis. Both standard users and power users benefit from adopting these APIs as they lower the language barrier of input styles and enable a standard layout of variables and data. These designs allow end-to-end interoperable programming of complex computations and provide best practices options by default.

Transformation of a dense metal–organic framework (MOF) to a highly porous form can radically improve its applications in drug loading. In this study, an environmentally friendly synthesis of potas...

Solid solutions, structurally ordered but compositionally disordered mixtures, can form for salts, metals, and even organic compounds. The NaCl-KCl system forms a solid solution at all compositions between 657{\deg}C and 505{\deg}C. Below a critical temperature of 505{\deg}C, the system exhibits a miscibility gap with coexisting Na-rich and K-rich rocksalt phases. We calculate the phase diagram in this region using the semi-grand canonical Widom method, which averages over virtual particle transmutations. We verify our results by comparison with free energies calculated from thermodynamic integration and extrapolate the location of the critical point. The calculations reproduce the experimental phase diagram remarkably well and illustrate how solid-solid equilibria and chemical potentials, including those at metastable conditions, can be computed for materials that form solid solutions., Comment: 10 pages, 9 figures

Solubility is a fundamental property of widespread significance. Despite its importance, its efficient and accurate prediction from first principles remains a major challenge. Here we propose a novel method to predict the solubility of molecules using a density of states (DOS) approach from classical molecular simulation. The method offers a potential route to solubility prediction for large (including drug-like) molecules over a range of temperatures and pressures, all from a modest number of simulations. The method was employed to predict the solubility of sodium chloride in water at ambient conditions, yielding a value of 3.77(5) mol kg-1. This is in close agreement with other approaches based on molecular simulation, the consensus literature value being 3.71(25) mol kg-1. The predicted solubility is about half of the experimental value, the disparity being attributed to the known limitation of the Joung-Cheatham force field model employed for NaCl. The proposed method also accurately predicted the NaCl model's solubility over the temperature range 298-373 K directly from the density of states data used to predict the ambient solubility.

Leaf rust occurs worldwide wherever wheat is grown. The current research was planned to evaluate the response of 37 wheat (Triticum aestivum) genotypes against leaf rust resistance under field conditions during crop season 2017-18.These genotypes were sown in augmented design with two meter long line sowing method with 30 cm row to row distance at research area of Agricultural Biotechnology Research Institute (ABRI), Ayub Agricultural Research Institute (AARI), Faisalabad, Pakistan. After every five genotypes, a line of rust spreader “Morocco” was sown. Moreover, the trial was also surrounded by planting two rows of spreader to increase the inoculum pressure. Data was recorded on the basis of leaf rust severity scale. Leaf rust severity response was variable among tested genotypes. Out of thirty-seven genotypes, five wheat lines were immune (no disease symptoms) i.e. 17BT007, 17BT013, 16BT008, 16BT010 and 16BT011. Seven lines were found to be resistant with AUDPC vales ranged 1-199. Response of ten lines was moderately resistant while five lines were categorized as moderately susceptible. Ten genotypes exhibited susceptible response against leaf rust with more than 600 AUDPC value. High values above 600 of AUDPC showed greater incidence of leaf rust on wheat plants while lower AUDPC values indicated resistance to leaf rust. Present research provided the resistant wheat lines to the breeders to incorporate them in their breeding program against leaf rust.

Free energies of crystals computed using a center of mass constraint require a finite-size correction, as shown in previous work by Polson et al. [J. Chem. Phys. 112, 5339-5342 (2000)]. Their reference system is an Einstein crystal with equal spring constants. In this paper, we extend the work of Polson et al. [J. Chem. Phys. 112, 5339-5342 (2000)] to the case of differing spring constants. The generalization is convenient for constraining the center of mass in crystals with atoms of differing masses, and it helps to optimize the free energy calculations. To test the theory, we compare the free energies of LiI and NaCl crystals from calculations with differing spring constants to those computed using equal spring constants. Using these center of mass finite size corrections, we compute the true free energies of these crystals for different system sizes to eliminate the intrinsic finite-size effects. These calculations help demonstrate the size of these finite-size corrections relative to other contributions to the absolute free energy of the crystals.

The identification of two step nucleation mechanisms considerably extended our understanding of crystal nucleation. Here, we report an analogous observation of a two-step mechanism but in 2-D for deposition of molecules to a growing crystal face. Using molecular dynamics simulations connected with the Kawska-Zahn approach, α-resorcinol precipitation from the vapor is treated at the low driving force regime. Growth at the faster growing (011) face reveals the deposition of molecules to form a disordered liquid-like layer. Strikingly, this apparently divergent (nonepitaxial) molecular arrangement does not represent self-poisoning which would lower the growth rate of the (011) face. On the contrary, more favorable attachment energy along with a disorder–order transition, akin to a two-step nucleation observed in 3-D systems, leads to growth rates that are about 20 times faster than the more standard mode association of molecules at the (011) face where the molecules readily align according to the crystal...

Polar crystals are characterized by an axis that has a nonzero dipole due to the nature of the molecular packing. For these crystals, the growth rates of the faces delineating the polar axis are generally expected to be equal. Recent experiments, however, have revealed a few exceptions where the growth of these faces from the vapor phase is asymmetric, a notable case being crystals of resorcinol. Here, we present the mechanics of resorcinol crystal growth from the melt for the hemihedral faces (011) and (011) delineating the polar axis as revealed by molecular dynamics simulations. The simulations reveal asymmetric growth consistent with experiment. The asymmetry is attributed to the slow-growing (011) face being less able to direct the correct alignment of the oncoming molecules and the presence of an alternate resorcinol conformation that readily incorporates into the lattice at this surface, serving to poison and retard subsequent growth. Putting the issue of the rogue conformation aside, the identif...

Secondary nucleation, wherein crystal seeds are used to induce crystallization, is widely employed in industrial crystallizations. Despite its significance, our understanding of the process, particularly at the molecular level, remains rudimentary. An outstanding question is why do a few seeds give rise to a many-fold increase in new crystals? Using molecular simulation coupled with experiments we have uncovered the molecular processes that give rise to this autocatalytic behavior. The simulations reveal formation of molecular aggregates in solution, which on coming in contact with the surface of the seed undergo nucleation to form new crystallites. These crystallites are weakly bound to the crystal surface and can be readily sheared by fluid, making the seed surfaces available again to repeat the process. Further, the new crystallites on development can in turn serve as seeds. This mechanistic insight will enable better control in engineering crystalline products to design.

In this communication, we developed a thermally stable, biocompatible, and colonically degradable hydrogel-based device [pectin-co-poly(MAA)] for oral delivery of 5-fluorouracil (5-FU) to treat colon cancer with minimal upper gastrointestinal invasion. Toward this end, ethylene glycol dimethacrylate (EGDMA) cross-linked hydrogels of pectin were synthesized. Methacrylic acid (MAA) was grafted to impart pH-responsive character, whereas benzoyl peroxide (BPO) was applied for simultaneous grafting and cross-linking polymerization. The hydrogels were characterized by Fourier transform infrared , thermogravimetric analysis, differential scanning calorimetry, and X-ray diffractometry. Scanning electron microscopic photographs were taken to analyze the surface morphology. Swelling behavior was analyzed to assess better performance of biodegradable hydrogels for optimized loading and release of the drug targeted to the colon. Gel fraction, swelling ratio, diffusion coefficient, drug loading, and cumulative release increased with an increase of pectin ratio and decreased with an increase of MAA and EGDMA ratio. Strategically, hydrogels with higher amounts of pectin were prepared for complete degradation in the colon. Our investigations indicate that pectin-co-poly(MAA) hydrogel is a suitable delivery system developed for oral delivery of the drug targeted to the colon.

While the solubility of a substance is a fundamental property of widespread significance, its prediction from first principles (starting from only the knowledge of the molecular structure of the solute and solvent) remains a challenge. Recently, we proposed a robust and efficient method to predict the solubility from the density of states of a solute-solvent system using classical molecular simulation. The efficiency, and indeed the generality, of the method has now been enhanced by extending it to calculate solution chemical potentials (rather than probability distributions as done previously), from which solubility may be accessed. The method has been employed to predict the chemical potential of Form 1 of urea in both water and methanol for a range of concentrations at ambient conditions and for two charge models. The chemical potential calculations were validated by thermodynamic integration with the two sets of values being in excellent agreement. The solubility determined from the chemical potentials for urea in water ranged from 0.46 to 0.50 mol kg−1, while that for urea in methanol ranged from 0.62 to 0.85 mol kg−1, over the temperature range 298–328 K. In common with other recent studies of solubility prediction from molecular simulation, the predicted solubilities differ markedly from experimental values, reflecting limitations of current forcefields.

Aqueous dispersions of nanoparticles (nanosuspensions) of poorly soluble drugs are an effective option for addressing issues of low and erratic bioavailability. They are, however, not attractive as dosage forms due to their predisposition to physical and chemical instability. Here we describe an effective method for isolating nanocrystals in solid form from a suspension, which opens up the possibility of formulating nanocrystals in solid dosage forms such as tablets. The method involves the use of carrier particles to adsorb and recover nanocrystals from a liquid suspension. The method is illustrated by using carrier particles of dibasic calcium phosphate to recover nanocrystals of ibuprofen and glibenclamide produced by both size reduction and crystallization. Respective recoveries of the nanocrystals were in excess of 90%. Powders of carrier-nanocrystal particles yielded dissolution rates similar to those of the native nanocrystals and substantially faster than marketed tablets and micronized suspensions of the drugs, confirming that the high surface area of the nanocrystals is retained during the adsorption process.

Nanocrystals have the potential to address the challenges of delivering drugs with low aqueous solubility. In this study, the use of low energy anti-solvent precipitation for producing nanocrystals has been investigated. Stable nanocrystals with uniform particle size were prepared for the three model compounds, glyburide, ibuprofen, and artemisinin, which are all practically insoluble in water and have diverse molecular structures and crystal packings. The choice of crystal growth inhibitors/stabilizers was found to be critical and specific for each drug. The effect of the process variables, temperature, stirring rate, and the solute solution infusion rate into the antisolvent, was rationalized in terms of how these factors influence the local supersaturation attained at the earliest stages of precipitation. The dissolution of the nanocrystals in aqueous media under physiological conditions was shown in all cases to occur almost instantaneously, being markedly more rapid than that observed for micronized ...

Additive manufacturing technologies offer exciting opportunities to rethink the process of designing and fabricating physical structures. This paper outlines initial work that seeks to extend existing AM capabilities, creating physically adaptive structures by exploiting processes of self-assembling materials. The paper details an investigation of self-assembling structures that can respond to different conditions by adapting their physical properties over time. The process uses electrolysis of seawater to demonstrate a proof-of concept of tuneable material structures, via crystal growth. Results demonstrate an aggregation-based multi-material system that is sensitive to changing environmental conditions. Material properties of grown structures have been analysed and illustrate that different materials can be created from an abundant base material (seawater) by manipulating environmental conditions (i.e. electrical current). It is found that turbulence is a useful property within these kinds of systems and that the physical properties of cathode scaffold structures have a significant impact in controlling material properties and resolution.

Transformations in the solid state are of considerable interest, both for fundamental reasons and because they underpin important technological applications. The interest spans a wide spectrum of disciplines and application domains. For pharmaceuticals, a common issue is unexpected polymorphic transformation of the drug or excipient during processing or on storage, which can result in product failure. A more ambitious goal is that of exploiting the advantages of metastable polymorphs (e.g. higher solubility and dissolution rate) while ensuring their stability with respect to solid state transformation. To address these issues and to advance technology, there is an urgent need for significant insights that can only come from a detailed molecular level understanding of the involved processes. Whilst experimental approaches at best yield time- and space-averaged structural information, molecular simulation offers unprecedented, time-resolved molecular-level resolution of the processes taking place. This review aims to provide a comprehensive and critical account of state-of-the-art methods for modelling polymorph stability and transitions between solid phases. This is flanked by revisiting the associated macroscopic theoretical framework for phase transitions, including their classification, proposed molecular mechanisms, and kinetics. The simulation methods are presented in tutorial form, focusing on their application to phase transition phenomena. We describe molecular simulation studies for crystal structure prediction and polymorph screening, phase coexistence and phase diagrams, simulations of crystal-crystal transitions of various types (displacive/martensitic, reconstructive and diffusive), effects of defects, and phase stability and transitions at the nanoscale. Our selection of literature is intended to illustrate significant insights, concepts and understanding, as well as the current scope of using molecular simulations for understanding polymorphic transitions in an accessible way, rather than claiming completeness. With exciting prospects in both simulation methods development and enhancements in computer hardware, we are on the verge of accessing an unprecedented capability for designing and developing dosage forms and drug delivery systems in silico, including tackling challenges in polymorph control on a rational basis.

The skin barrier is fundamental to terrestrial life and its evolution; it upholds homeostasis and protects against the environment. Skin barrier capacity is controlled by lipids that fill the extracellular space of the skin's surface layer-the stratum corneum. Here we report on the determination of the molecular organization of the skin's lipid matrix in situ, in its near-native state, using a methodological approach combining very high magnification cryo-electron microscopy (EM) of vitreous skin section defocus series, molecular modeling, and EM simulation. The lipids are organized in an arrangement not previously described in a biological system-stacked bilayers of fully extended ceramides (CERs) with cholesterol molecules associated with the CER sphingoid moiety. This arrangement rationalizes the skin's low permeability toward water and toward hydrophilic and lipophilic substances, as well as the skin barrier's robustness toward hydration and dehydration, environmental temperature and pressure changes, stretching, compression, bending, and shearing.Journal of Investigative Dermatology advance online publication, 26 April 2012; doi:10.1038/jid.2012.43.

The freezing of water to ice is fundamentally important to fields as diverse as cloud formation to cryopreservation. At ambient conditions, ice is considered to exist in two crystalline forms: stable hexagonal ice and metastable cubic ice. Using X-ray diffraction data and Monte Carlo simulations, we show that ice that crystallizes homogeneously from supercooled water is neither of these phases. The resulting ice is disordered in one dimension and therefore possesses neither cubic nor hexagonal symmetry and is instead composed of randomly stacked layers of cubic and hexagonal sequences. We refer to this ice as stacking-disordered ice I. Stacking disorder and stacking faults have been reported earlier for metastable ice I, but only for ice crystallizing in mesopores and in samples recrystallized from high-pressure ice phases rather than in water droplets. Review of the literature reveals that almost all ice that has been identified as cubic ice in previous diffraction studies and generated in a variety of ways was most likely stacking-disordered ice I with varying degrees of stacking disorder. These findings highlight the need to reevaluate the physical and thermodynamic properties of this metastable ice as a function of the nature and extent of stacking disorder using well-characterized samples.

To explore the use of crystal inter-planar d-spacings and slip-plane interaction energies for predicting and characterising mechanical properties of crystalline solids. Potential relationships were evaluated between mechanical properties and inter-planar d-spacing, inter-planar interaction energy, and dispersive surface energy as determined using inverse gas chromatography (IGC) for a set of pharmaceutical materials. Inter-planar interaction energies were determined by molecular modelling. General trends were observed between mechanical properties and the largest inter-planar d-spacing, inter-planar interaction energies, and IGC dispersive surface energy. A number of materials showed significant deviations from general trends. Weak correlations and outliers were rationalised. Results suggest that the highest d-spacing of a material could serve as a first-order indicator for ranking mechanical behaviour of pharmaceutical powders, but with some reservation. Inter-planar interaction energy normalised for surface area shows only a weak link with mechanical properties and does not appear to capture essential physics of deformation. A novel framework linking mechanical properties of crystals to the distinct quantities, slip-plane energy barrier and inter-planar interaction (detachment) energy is proposed.

Two force fields, the GROMOS53A5/53A6 (united atom) and the AMBER95 (all atom) parameter sets, coupled with partial atomic charges derived from quantum mechanical calculations were evaluated for their ability to reproduce the known crystalline forms of the polyols mannitol and sorbitol. The force fields were evaluated using molecular dynamics simulations at 10 K (which is akin to potential energy minimization) with the simulation cell lengths and angles free to evolve. Both force fields performed relatively poorly, not being able to simultaneously reproduce all of the crystal structures within a 5% deviation level. The parameter sets were then systematically optimized using sensitivity analysis, and a revised AMBER95 set was found to reproduce the crystal structures with less than 5% deviation from experiment. The stability of the various crystalline forms for each of the parameter sets (original and revised) was then assessed in extended MD simulations at 298 K and 1 bar covering 1 ns simulation time. The AMBER95 parameter sets (original and revised) were found to be effective in reproducing the crystal structures in these more stringent tests. Remarkably, the performance of the original AMBER95 parameter set was found to be slightly better than that of the revised set in these simulations at 298 K. The results of this study suggest that, whenever feasible, one should include molecular simulations at elevated temperatures when optimizing parameters. © 2010 American Chemical Society.

Molecular dynamics simulations reveal that the key factors that determine the ability of an additive to modulate crystal nucleation are the strength of its interaction with the solute, its disruptive ability (which may be based on steric, entropic, or energetic effects), and interfacial properties, along with its ability to serve as a template for nucleation (see snapshot of an emerging nucleus with a single-particle additive: black spheres).

Transmembrane pore formation is central to many biological processes such as ion transport, cell fusion, and viral infection. Furthermore, pore formation in the ceramide bilayers of the stratum corneum may be an important mechanism by which penetration enhancers such as dimethylsulfoxide (DMSO) weaken the barrier function of the skin. We have used the potential of mean constraint force (PMCF) method to calculate the free energy of pore formation in ceramide bilayers in both the innate gel phase and in the DMSO-induced fluidized state. Our simulations show that the fluid phase bilayers form archetypal water-filled hydrophilic pores similar to those observed in phospholipid bilayers. In contrast, the rigid gel-phase bilayers develop hydrophobic pores. At the relatively small pore diameters studied here, the hydrophobic pores are empty rather than filled with bulk water, suggesting that they do not compromise the barrier function of ceramide membranes. A phenomenological analysis suggests that these vapor pores are stable, below a critical radius, because the penalty of creating water-vapor and tail-vapor interfaces is lower than that of directly exposing the strongly hydrophobic tails to water. The PMCF free energy profile of the vapor pore supports this analysis. The simulations indicate that high DMSO concentrations drastically impair the barrier function of the skin by strongly reducing the free energy required for pore opening.

We address the possibility of being able to induce the trafficking of salt ions and other solutes across cell membranes without the use of specific protein-based transporters or pumps. On the basis of realistic atomic-scale molecular dynamics simulations, we demonstrate that transmembrane ionic leakage can be initiated by chemical means, in this instance through addition of dimethyl sulfoxide (DMSO), a solvent widely used in cell biology. Our results provide compelling evidence that the small amphiphilic solute DMSO is able to induce transient defects (water pores) in membranes and to promote a subsequent diffusive pore-mediated transport of salt ions. The findings are consistent with available experimental data and offer a molecular-level explanation for the experimentally observed activities of DMSO solvent as an efficient penetration enhancer and a cryoprotectant, as well as an analgesic. Our findings suggest that transient pore formation by chemical means could emerge as an important general principle for therapeutics.

The fatty acid oleic acid (OA) is known to modulate the structure of membranes, which forms the basis for a number of its important applications including its use as a therapeutic supplement to reduce the risk of cardiovascular disease, in molecule delivery systems such as liposomes, and as a skin permeability enhancer. While a number of studies have investigated the effect of OA on lipid membranes, our understanding of its mechanisms of action at the molecular level remains rudimentary. We have carried out molecular dynamics simulations using coarse-grained models to investigate the interactions of OA at a range of concentrations with a dipalmitoylphosphatidylcholine (DPPC) bilayer in the liquid-crystalline phase. We have also investigated the relative permeability of the bilayers to model hydrophilic and hydrophobic penetrants by means of chemical potential calculations. The results indicate that OA is able to disperse homogeneously into the bilayer at all concentrations without much perturbation. OA appears to slightly weaken the lateral forces between lipid headgroups, and as the concentration of OA increases this manifests itself as a slight decrease in the area compressibility modulus and a minor increase in the diffusion rate of the OA molecules. While the chemical potential profiles showed little or no variation as a function of OA concentration, the frequency of water permeation events was found to double, indicating some OA-induced permeability enhancement. The study suggests that physiological effects of OA are probably more subtle rather than via gross perturbation of the structure, or that its significant effects are restricted to more condensed membrane structures such as the gel phase.

Dimethyl sulfoxide (DMSO) is a small amphiphilic molecule which is widely employed in cell biology as an effective penetration enhancer, cell fusogen, and cryoprotectant. Despite the vast number of experimental studies, the molecular basis of its action on lipid membranes is still obscure. A recent simulation study employing coarse-grained models has suggested that DMSO induces pores in the membrane (Notman, R.; Noro, M.; O'Malley, B.; Anwar, J. J. Am. Chem. Soc. 2006, 128, 13982-13983). We report here the molecular mechanism for DMSO's interaction with phospholipid membranes ascertained from atomic-scale molecular dynamics simulations. DMSO is observed to exhibit three distinct modes of action, each over a different concentration range. At low concentrations, DMSO induces membrane thinning and increases fluidity of the membrane's hydrophobic core. At higher concentrations, DMSO induces transient water pores into the membrane. At still higher concentrations, individual lipid molecules are desorbed from the membrane followed by disintegration of the bilayer structure. The study provides further evidence that a key aspect of DMSO's mechanism of action is pore formation, which explains the significant enhancement in permeability of membranes to hydrophilic molecules by DMSO as well as DMSO's cryoprotectant activity. The reduction in the rigidity and the general disruption of the membrane induced by DMSO are considered to be prerequisites for membrane fusion processes. The findings also indicate that the choice of DMSO concentration for a given application is critical, as the concentration defines the specific mode of the solvent's action. Knowledge of the distinct modes of action of DMSO and associated concentration dependency should enable optimization of current application protocols on a rational basis and also promote new applications for DMSO.

Differential growth: The growth of crystals of α-resorcinol (see picture; C gray, H white, O red) from the vapor phase is asymmetric along the polar axis. By means of molecular-dynamics simulations, the slower growth at the (011) polar surface is traced back to conformational change of the molecule and to surface reconstruction, which may be a general phenomenon in polar crystals.

Martensitic transformations are of considerable technological importance, a particularly promising application being the possibility of using martensitic materials, possibly proteins, as tiny machines. For organic crystals, however, a molecular level understanding of such transformations is lacking. We have studied a martensitic-type transformation in crystals of the amino acid DL-norleucine using molecular dynamics simulation. The crystal structures of DL-norleucine comprise stacks of bilayers (formed as a result of strong hydrogen bonding) that translate relative to each other on transformation. The simulations reveal that the transformation occurs by concerted molecular displacements involving entire bilayers rather than on a molecule-by-molecule basis. These observations can be rationalized on the basis that at sufficiently high excess temperatures, the free energy barriers to concerted molecular displacements can be overcome by the available thermal energy. Furthermore, in displacive transformations, the molecular displacements can occur by the propagation of a displacement wave (akin to a kink in a carpet), which requires the molecules to overcome only a local barrier. Concerted molecular displacements are therefore considered to be a significant feature of all displacive transformations. This finding is expected to be of value toward developing strategies for controlling or modulating martensitic-type transformations.

The lipids of the topmost layer of the skin, the stratum corneum, represent the primary barrier to molecules penetrating the skin. One approach to overcoming this barrier for the purpose of delivery of active molecules into or via the skin is to employ chemical permeability enhancers, such as dimethylsulfoxide (DMSO). How these molecules exert their effect at the molecular level is not understood. We have investigated the interaction of DMSO with gel-phase bilayers of ceramide 2, the predominant lipid in the stratum corneum, by means of molecular dynamics simulations. The simulations satisfactorily reproduce the phase behavior and the known structural parameters of ceramide 2 bilayers in water. The effect of DMSO on the gel-phase bilayers was investigated at various concentrations over the range 0.0−0.6mol fraction DMSO. The DMSO molecules accumulate in the headgroup region and weaken the lateral forces between the ceramides. At high concentrations of DMSO (≥0.4mol fraction), the ceramide bilayers undergo a phase transition from the gel phase to the liquid crystalline phase. The liquid-crystalline phase of ceramides is expected to be markedly more permeable to solutes than the gel phase. The results are consistent with the experimental evidence that high concentrations of DMSO fluidize the stratum corneum lipids and enhance permeability.

We employ the cleaving approach to calculate directly the ice Ih-water interfacial free energy for the simple models of water, TIP4P, TIP4P-Ew, and TIP5P-E, with full electrostatic interactions evaluated via the Ewald sums. The results are in good agreement with experimental values, but lower than previously obtained for TIP4P-Ew and TIP5P-E by indirect methods. We calculate the interfacial free energies for basal, prism, and {112̅0} interfaces and find that the anisotropy of the TIP5P-E model is different from that of the TIP4P models. The effect of including full electrostatic interactions is determined to be smaller than 10% compared to the water models with damped Coulomb interactions, which indicates that the value of the ice-water interfacial free energy is determined predominantly by the short-range packing interaction between water molecules. We also observe a strong linear correlation between the interfacial free energy and the melting temperature of different water models.

We show that graphene nano-sheets, when appropriately functionalised, can form self-assembling nanocontainers which may be opened or closed using a chemical trigger such as pH or polarity of solvent. Conceptual design rules are presented for different container structures, whose ability to form and encapsulate guest molecules is verified by molecular dynamics simulations. The structural simplicity of the graphene nanocontainers offers considerable scope for scaling the capacity, modulating the nature of the internal environment, and defining the trigger for encapsulation or release of the guest molecule(s). This design study will serve to provide additional impetus to developing synthetic approaches for selective functionalisation of graphene.

Sarah Price opened a general discussion of the paper by Sven Schroeder: I have been generating the thermodynamically plausible crystal structures of organic molecules for many years, and back in 2004 we did a crystal structure prediction (CSP) study on imidazole1 and found that it was relatively straightforward. Following your paper, we have reclassified the low energy structures according to the tilt within the hydrogen-bonded chain and the relative direction of the chains. Although the observed structure was the global minimum, two other structures with a displacement of otherwise identical layers are very close in energy. Do you think that if imidazole had crystallised in one of these alternative structures it would be distinguishable by NEXAFS? This would be a very sensitive test of whether NEXAFS combined with CSP could be used in characterising crystal structures.

d,l-Norleucine is one of only a few molecules whose crystals exhibit a martensitic or displacive-type phase transformation where the emerging phase shows a topotaxial relationship with the parent phase. The molecular mechanism for such phase transformations, particularly in molecular crystals, is not well understood. Crystalline phases that exhibit displacive phase transitions tend to be very similar in structure and energy. Consequently, the development of a force field for such phases is challenging as the phase behavior is determined by subtle differences in their lattice energies and entropies. We report an approach for developing a force field for such phases with an application to d,l-norleucine. The proposed procedure includes calculation of the phase diagram of the crystalline phases as a function of temperature to identify the best force field. d,l-Norleucine also presents an additional problem since in the solid state it exists as a zwitterion that is unstable in vacuo and therefore cannot be characterized using high-level ab initio calculations in the gas phase. However, a stable zwitterion could be obtained using Onsager's reaction-field continuum model for a solvent (SCRF) using both Hartree-Fock and density functional theory. A number of force fields and the various sets of partial charges obtained from the SCRF calculations were screened for their ability to reproduce the crystal structures of the two known phases, alpha and beta, of d,l-norleucine. Selected parameter sets were then employed in free energy minimizations to identify the best set on the basis of a correct prediction of the alpha-beta phase transition. The Williams' nonbonded parameters combined with partial charges from SCRF-Polarized Continuum Model calculation were found to reproduce the structures of the phases accurately and also maintained their stability in extended molecular dynamics simulations in the Parrinello-Rahman constant stress ensemble. Moreover, we were also able to successfully simulate the phase transformation of the beta- to the alpha-phase. The identified force field should enable detailed studies of the phase transformations exhibited by crystals of d,l-norleucine and hence enhance our understanding of martensitic-type transformations in molecular crystals.

We have carried out simulations of the compaction of model granular beds constructed from Lennard-Jones (LJ) particles using nonequilibrium molecular dynamics (MD). The systems simulated comprised a model die containing either a single granule or many granules that were compacted uniaxially by a vertically moving top wall. The simulations while atomistic in nature can also be considered to have a mesoscopic significance in that the primary LJ particles represent coarse-grained units that comprise a realistically sized macroscopic granule. This representation enables plastic deformation of the individual granules as well as fusion between granules to be modeled at a fundamental level. As a granule is compressed, the constituent particles move past each other, giving rise to its deformation. In a multigranular system, at the points of contact between granules, the surface particles on adjacent granules interact with each other and reproduce many of the features of intergranular bonding observed in real systems. The proposed model, although simple, captures the essential physics of the compaction process in a transparent way. It is able to encompass the transition from mainly elastic to plastic deformation, which is instrumental in affecting the quality of real tablets. Using the developed model, we have explored the effects of compression rate on the deformation behavior of the powder column, the microstructure, and the integrity of the formed tablet. The simulations reproduced a number of well-known effects found in tableting. At high compaction speeds and increased extent of final compaction the system manifested a strong elastic response, giving rise to a tendency for the tablets to laminate on decompaction. Slower compaction speeds allowed more time for greater internal rearrangement or plastic deformation and produced a more structurally uniform and stable tablet at the end of the cycle. The simulations also revealed the underlying cause for high-pressure "hot" spots and regions of weak interaction within the tablet where failure can occur. These points or regions invariably corresponded to incoherent interfaces between granule boundaries, and in some instances to interstitial atoms. The mechanical stability of the tablet was found to depend on the effectiveness of the consolidation of the granules, enhanced effectiveness being characterized by more coherent granule boundaries, resulting in a more uniform pressure distribution and stronger granule-granule interactions.

We have carried out nonequilibrium molecular dynamics simulations of the compaction of a single three-dimensional granule composed of over 1000 Lennard-Jones (LJ) particles. The granule was contained within an orthorhombic box with repulsive walls and deformed by a vertically moving top wall. The compaction cycle adopted was intended to mimic the procedure employed in industrial tabletting processes, by compressing the granule during the downward movement of the top wall (compaction) followed by an upward movement of the top wall (decompaction). We have explored the effects of different compression rates on the deformation, microstructure, and the final integrity of the granule. Although the simulations are formally atomistic, we believe a mesoscopic significance can be attached to the results that makes them relevant to the larger scale compaction involved in industrially relevant processes. The cluster representation of the granule allows for significant deformation during the process, and the simulations reproduce a number of well-known effects found in the pharmaceutical tabletting and other literature. Rapid compaction resulted in an essentially elastic response and even break up of the formed tablet during the decompaction stage, an effect known as lamination. Slower compaction speeds, which enabled greater internal rearrangement of the LJ particles through plastic deformation, produced a more structurally uniform tablet at the end of the cycle. For the faster compaction speed the top wall moved away faster than the compacted material could recover, giving rise to misleadingly low values of the apparent elastic response of the material as measured by the force from the material on the top wall. We believe this could be an important issue when interpreting experimental data. These simulations were able to capture the transition between the fast and slow compaction rate regimes and reveal some rudiments of the lamination problem that plagues the industrial process of tabletting.

This paper proposes the development of a drug product Manufacturing Classification System (MCS) based on processing route. It summarizes conclusions from a dedicated APS conference and subsequent discussion within APS focus groups and the MCS working party. The MCS is intended as a tool for pharmaceutical scientists to rank the feasibility of different processing routes for the manufacture of oral solid dosage forms, based on selected properties of the API and the needs of the formulation. It has many applications in pharmaceutical development, in particular, it will provide a common understanding of risk by defining what the "right particles" are, enable the selection of the best process, and aid subsequent transfer to manufacturing. The ultimate aim is one of prediction of product developability and processability based upon previous experience. This paper is intended to stimulate contribution from a broad range of stakeholders to develop the MCS concept further and apply it to practice. In particular, opinions are sought on what API properties are important when selecting or modifying materials to enable an efficient and robust pharmaceutical manufacturing process. Feedback can be given by replying to our dedicated e-mail address (mcs@apsgb.org); completing the survey on our LinkedIn site; or by attending one of our planned conference roundtable sessions.

The mechanism by which solvent exerts its effect during the process of crystallization is poorly understood. An important and ongoing problem is the uneven growth of the faces {011} and {011} of α-resorcinol in water. Growth occurs mainly at the {011} surface. In an attempt to determine the mechanism, molecular-dynamics simulations have been carried out of the two surfaces in contact with water. The dynamical properties of the water close to the surface as well as the overall interaction energies of the water with the respective faces have been calculated. The strongest water-binding sites have also been determined and energetically characterized. The data indicate that the adsorption of water molecules is stronger at the slower growing {011} face, with the strongest binding occurring at specific sites on this face. The motion of the water molecules in the surface layer at this face is also more localized and restricted compared with that at the faster growing {011} face. The binding sites at the {0...

The crystal structure of sulfathiazole [4-amino-N-(2,3-dihydro-2-thiazolylidene)benzenesulfonamide, C9H9N3O2S] polymorphic form V has been determined from high-resolution synchrotron X-ray powder diffraction data. The structure is monoclinic, space groupP21/n,Z= 8, with two molecules in the asymmetric unit. The unit-cell dimensions area= 14.3296 (3),b= 15.2733 (2),c= 10.4428 (2) Å and β = 91.052 (1)° with cell volumeV= 2285.13 (8) Å3. The structure has been solved by direct methods without recourse to any computational modelling techniques for generating possible structures. The unrefined structure obtained from direct methods gave anRwpvalue of 36.5%. Refinement of atomic and displacement parameters yielded a finalRwpof 12.54% (Rp= 9.37%). The conformations of the two molecules in the asymmetric unit are nearly identical and very similar to that found in other forms of sulfathiazole. The molecular packing is characterized by molecular sheets lying perpendicular to theaaxis. Each sheet is two molecules thick, being integrated by hydrogen bonding. With 16 non-H atoms in the molecule and two molecules in the asymmetric unit, this structure represents a further advance in terms of the complexity of an organic structure solved from X-ray powder diffraction data.

The early stages of crystallization are not fully understood, a particularly challenging problem being crystallization from solution. The processes involved at an atomic level remain elusive to experiment. Furthermore, crystallization from solution has been thought to be inaccessible by atomistic computer simulations. This study demonstrates that crystallization from solution can in fact be simulated using the method of molecular dynamics for a model solute/solvent system consisting of atomic species characterized by the Lennard-Jones potential function. The model has been applied to look at the effects of varying supersaturation and of inclusion of a simple inhibitor in the system. The behavior of the model is in accord with experiment. In general, increasing supersaturation causes earlier onset of crystallization. Crystallization in highly supersaturated systems involves liquid-liquid phase separation followed by nucleation in the solute phase. The nucleation event in such systems does not appear to be influenced by the solvent. Inclusion of inhibitors retards the onset. Additionally, extensive solute clustering is observed. The crystallization model and variations on it, as well as step by step extension to realistic systems, should enable further testing and development of theory of crystal nucleation and growth and provide insights of technological importance.

Poly(d,l-lactide) microspheres with progesterone loadings of 0, 10, 20, 30 and 50% w/w were manufactured using an interrupted solvent evaporation process. Spherical microspheres with loadings close to the theoretical values were produced. The glass transition of the polymer could be identified by a step change in the heat capacity measured by TMDSC. Progesterone was found to plasticise the glass transition temperature at contents of 20% w/w or less. At a 30% loading, cold crystallisation of progesterone was seen indicating that an amorphous form of the drug was present; these microspheres were found to exhibit a pitted surface. TMDSC of the 50% progesterone samples suggested that most of the drug was present as crystals. This was supported by the SEM and PXRD results.