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AmberTools is a free and open-source collection of programs used to set up, run, and analyze molecular simulations. The newer features contained within AmberTools23 are briefly described in this Application note.

We report the development and testing of new integrated cyberinfrastructure for performing free energy simulations with generalized hybrid quantum mechanical/molecular mechanical (QM/MM) and machine learning potentials (MLPs) in Amber. The Sander molecular dynamics program has been extended to leverage fast, density-functional tight-binding models implemented in the DFTB+ and xTB packages, and an interface to the DeePMD-kit software enables the use of MLPs. The software is integrated through application program interfaces that circumvent the need to perform "system calls" and enable the incorporation of long-range Ewald electrostatics into the external software's self-consistent field procedure. The infrastructure provides access to QM/MM models that may serve as the foundation for QM/MM–ΔMLP potentials, which supplement the semiempirical QM/MM model with a MLP correction trained to reproduce ab initio QM/MM energies and forces. Efficient optimization of minimum free energy pathways is enabled through a new surface-accelerated finite-temperature string method implemented in the FE-ToolKit package. Furthermore, we interfaced Sander with the i-PI software by implementing the socket communication protocol used in the i-PI client–server model. The new interface with i-PI allows for the treatment of nuclear quantum effects with semiempirical QM/MM–ΔMLP models. The modular interoperable software is demonstrated on proton transfer reactions in guanine-thymine mispairs in a B-form deoxyribonucleic acid helix. The current work represents a considerable advance in the development of modular software for performing free energy simulations of chemical reactions that are important in a wide range of applications. [ABSTRACT FROM AUTHOR]

Degradable polymeric Biomaterials, such as polylactic acid, are widely used in medical field as bioresorbable implant coatings. More recently, stent covers, implantable tubes or wound dressings made from electrospun nanofibers have been developed. In order to tailor the material for specific applications, dedicated fine-tuning procedures are required. To modify fiber interconnection or porosity, solvents or their dilutions are applicable. In this work, the effect of differently diluted protic and aprotic-polar solvents on electrospun poly-L-lactic acid (PLLA) nonwovens was investigated via immersion or vapor exposure. Fiber adhesion was observed with protic solvents. Fiber destruction and increased polymer crystallinity was observed with aprotic polar solvents. The immersion duration revealed to be far more irrelevant than solvent dilution. None of the tested solvents affected molecular weight. This opens up significant research potential to replace halogenated solvents as a cornerstone of eco-friendly “green” electrospinning processes. The results of this study are suggesting that biomaterials with desired properties can be produced in a targeted manner.

The reactive uptake of N2O5 to aqueous aerosol is a major loss channel for nitrogen oxides in the troposphere. Despite its importance, a quantitative picture of the uptake mechanism is missing. Here we use molecular dynamics simulations with a data-driven many-body model of coupled-cluster accuracy to quantify thermodynamics and kinetics of solvation and adsorption of N2O5 in water. The free energy profile highlights that N2O5 is selectively adsorbed to the liquid-vapor interface and weakly solvated. Accommodation into bulk water occurs slowly, competing with evaporation upon adsorption from gas phase. Leveraging the quantitative accuracy of the model, we parameterize and solve a reaction-diffusion equation to determine hydrolysis rates consistent with experimental observations. We find a short reaction-diffusion length, indicating that the uptake is dominated by interfacial features. The parameters deduced here, including solubility, accommodation coefficient, and hydrolysis rate, afford a foundation for which to consider the reactive loss of N2O5 in more complex solutions.

Cytochrome bd-type quinol oxidase is an important metalloenzyme that allows many bacteria to survive in low oxygen conditions. Since bd oxidase is found in many prokaryotes but not in eukaryotes, it has emerged as a promising bacterial drug target. Examples of organisms containing bd oxidases include the Mycobacterium tuberculosis (Mtb) bacterium that causes tuberculosis (TB) in humans, the Vibrio cholerae bacterium that causes cholera, the Pseudomonas aeruginosa bacterium that contributes to antibiotic resistance and sepsis, and the Campylobacter jejuni bacterium that causes food poisoning. Escherichia coli (E. coli) is another organism exhibiting the cytochrome bd oxidase. Since it has the highest sequence identity to Mtb (36%) and we are ultimately interested in finding drug targets for TB, we have built parameters for the E. coli bd oxidase (Protein Data Bank ID number: 6RKO) that are compatible with the all-atom Amber ff14SB force field for molecular dynamics (MD) simulations. Specifically, we built parameters for the three heme cofactors present in all species of bacterial cytochrome bd-type oxidases (heme b 558 , heme b 595 , and heme d) along with their axial ligands. This data report includes the parameter and library files that can be used with Amber's LEaP program to generate input files for MD simulations using the Amber software package. We also provide the PDB data files of the initial model both by itself and solvated with TIP3P water molecules and counterions.

Electrospinning, a standard technique for producing nonwoven fabrics, is widely used in the biomedical field. Due to local electric fields, fiber deposition is influenced by 3D surface structure of metallic collectors. For complex shaped structures, predicting the deposition and orientation of the fibers remains challenging. Investigations on well-defined structures permit a more detailed insight. In this study, metal blocks with round, slit and square holes of various sizes and depths were fabricated and covered with a thin layer of polymer fibers. The fiber arrangement of the layer was investigated by different microscopic methods. Analysis of the results showed less deposition on round holes and well-bridged aligned fibers on gaps which were less than four times wide as deep. Experimental results confirmed the theoretical predictions. Considering these findings, further work can be addressed to specific collector design to attain targeted fiber deposition.

Background: Childhood blindness remains a neglected issue in eye care within low-income countries, with congenital and juvenile cataracts being the most common treatable causes. This study aims to investigate the factors influencing the management of congenital and juvenile bilateral cataracts, provide data on general outcomes and postoperative findings, and discuss treatment in a low-income country context. Methods: In this prospective study, data from clinical care were continuously entered into a database, and one follow-up examination of a cohort of 91 patients with congenital and juvenile bilateral cataracts in Kinshasa, Democratic Republic of the Congo, was conducted. Multiple factors that affect the first clinical presentation, the clinical management, and outcome were investigated. Results: Most patients (88.5%) who received medical treatment were identified by cataract finders. A patient's presentation time was independent of the parent's education, social status, income, and sex of the child. The median age at first presentation was 5.8 years (ranging from 0 days to 17.3 years). The best visual acuity outcomes were achieved by patients who underwent surgery during early childhood. According to WHO grades and on an eye level basis, 51.1% (93 out of 182 eyes) showed improvement, while 34.6% (63 eyes) had unchanged results post-surgery. Among the cases without improvement, 76.2% were blind prior to surgery. Postoperative findings were observed in 56% of the patients, with secondary cataracts being the most common, affecting 26.37% of the operated eyes. Conclusions: Optimal management of childhood cataracts involves early identification, efficient hospital infrastructure, high-quality medical care, and long-term follow up. In sub-Saharan Africa, this approach must be adapted to the context of available resources, which differs significantly from those in high- and middle-income countries. [ABSTRACT FROM AUTHOR]

Metal/water interfaces are key in many natural and industrial processes, such as corrosion, atmospheric, or environmental chemistry. Even today, the only practical approach to simulate large interfaces between a metal and water is to perform force-field simulations. In this work, we propose a novel force field, GAL17, to describe the interaction of water and a Pt(111) surface. GAL17 builds on three terms: (i) a standard Lennard-Jones potential for the bonding interaction between the surface and water, (ii) a Gaussian term to improve the surface corrugation, and (iii) two terms describing the angular dependence of the interaction energy. The 12 parameters of this force field are fitted against a set of 210 adsorption geometries of water on Pt(111). The performance of GAL17 is compared to several other approaches that have not been validated against extensive first-principles computations yet. Their respective accuracy is evaluated on an extended set of 802 adsorption geometries of H2O on Pt(111), 52 geometries derived from icelike layers, and an MD simulation of an interface between a c(4 × 6) Pt(111) surface and a water layer of 14 Å thickness. The newly developed GAL17 force field provides a significant improvement over previously existing force fields for Pt(111)/H2O interactions. Its well-balanced performance suggests that it is an ideal candidate to generate relevant geometries for the metal/water interface, paving the way to a representative sampling of the equilibrium distribution at the interface and to predict solvation free energies at the solid/liquid interface.

Electrospinning is used for producing nonwovens for medical polymer-based implants, such as prosthetic valves or covered scaffolds. In this study, nonwovens for prosthetic venous valves are investigated regarding their morphology and mechanics in physiological medium. Spinning molds were developed based on previous venous valve leaflet designs, 3D printed in different sizes and covered with electrospun nonwovens. Samples were stored in a physiological 0.9% saline at 37°C to investigate the influence of fiber rearrangement and swelling in medium for several weeks. Two different nonwovens of thermoplastic silicone-based polycarbonaturethane (TSPCU) were compared. Tensile test results show that storage in medium has a relevant influence on the mechanical properties. SEM images of TSPCU show substantially increased fiber diameters after 8 days stored in medium. After detaching the valve leaflet nonwovens from the molds, shrinkage of the material of approximately 12% was detected. A suitable valve size could be identified for joining with the stent structure into an interventional prosthetic venous valve. The results demonstrate the influence of storage conditions on the morphological and mechanical properties of electrospun TSPCU nonwovens. For development and dimensioning of venous valve leaflets, this change in mechanical behavior and possible shrinkage of the material has to be considered.

Electrospinning (ES) is a suitable and cost effective method to mimic the chemical composition, morphology, and functional surface of natural tissues, for example of the nervous, dermal, vascular, and musculoskeletal systems. This technique is a versatile tool to obtain tailored fibrous scaffolds from various polymer materials. By varying the diameter, porosity, orientation, layering, surface structuring, mechanical properties and biodegradability of the fibers the properties can be adapted for specific applications ranging from implantable medical devices to wound repair and protective clothing. Especially the combination of different polymer types offers a high potential. In this study electrospun two-component nonwoven structures of thermoplastic copolyester elastomer (TPC-ET) and bioresorbable polylactide (PLLA) were fabricated, using different ES setups. A comparative evaluation in terms of porosity, thermal and mechanical properties as well as required fabrication effort, was performed. Nonwovens made from polymer blends and coaxial spun core-sheath fibers showed similar tensile strength, which was higher than dual electrospun fabrics. Porosity was found to be in the range of 80 - 90%. By modifying the polymer solution and process parameters multicomponent nonwoven structures with tailored properties and drug release profiles can be manufactured.

Electrospun nonwovens are widely applied in biomedicine and various other fields. For control of the manufacturing process and quality assurance Scanning electron microscopy (SEM) imaging is one standard practice. In this study, statistical datasets of 60 SEM images of three nonwoven samples were evaluated using Gaussian fit to obtain numerical results of their fiber diameter distributions. The question of how much effort is required for acceptable imaging and processing is being discussed. As determined here, for reliable statistics, a minimum surface area of the nonwoven has to be evaluated. The fiber diameter should be in a range of approximately 2 - 3% of the edge length of the square equivalent of the evaluated image area, using sufficiently magnified SEM images, in which the fiber diameter is imaged over at least 30 pixels.

We re-investigate the image charge model of Iori and Corni (Iori and Corni, J. Comput. Chem. 2008, 29, 1656). We find that a simple symmetrization of their model allows to obtain quantitatively correct results for the electrostatic interaction of a water molecule with a metallic surface. This symmetrization reduces the magnitude of the electrostatic interaction to less than 10% of the total interaction energy. © 2017 Wiley Periodicals, Inc.

A two-step method for investigating the stiffnesses and failure loads of vertebral bodies is presented. It is based on the representation of the spine in a global finite element model of structural elements. A detailed model of two interconnected vertebrae and an intervertebral disc was implemented. Calculations on this model are shown which illustrate the dependencies of structural stiffnesses on vertebral body properties. These structural stiffnesses can then be used to represent the spine in the global model.

Fiber materials offer a high potential for improving the surface characteristics of medical implants. For quality assurance of nano- and microfiber structures the morphology is inspected by Scanning Electron Microscopy (SEM) as a standard method. Vast quantities of image data have to be evaluated. Usual practice for obtaining the fiber diameters is the manually setting of measurement points. The software DiameterJ which runs as plugin in ImageJ automatically computes fiber diameters. Here we investigated its capabilities and limitations by comparing the evaluation of selected sample SEM images of electrospun fibers. In this study the fibers of three examplary images specified by different contrast and fiber morphology were analyzed by using varied segmentation algorithms. The results are displayed in bar charts of frequency distribution. Additionally the computed fiber diameters were compared to manual measurements. Depending on various image properties the segmentation process works more or less reliable, and fault data of incomplete segmented fibers are computed. Often the results are eligible, but frequently DiameterJ generates data resembling to thin fibers, which are not present in the image. In some cases the peaks of fault data are much higher than peaks of real fibers. In consequence misinterpretation of data cannot be avoided. DiameterJ is a validated tool with the ability to generate reliable results. Future work on improving the segmentation algorithms can refine computed evaluation.

Cisplatin (cDDP) is known to bind to the CXXC motif of proteins containing a ferrodoxin-like fold but little is known about its ability to interact with other Cu-binding proteins. MEK1/2 has recently been identified as a Cu-dependent enzyme that does not contain a CXXC motif. We found that cDDP bound to and inhibited the activity of recombinant MEK1 with an IC50 of 0.28 μM and MEK1/2 in whole cells with an IC50 of 37.4 μM. The inhibition of MEK1/2 was relieved by both Cu+1 and Cu+2 in a concentration-dependent manner. cDDP did not inhibit the upstream pathways responsible for activating MEK1/2, and did not cause an acute depletion of cellular Cu that could account for the reduction in MEK1/2 activity. cDDP was found to bind MEK1/2 in whole cells and the extent of binding was augmented by supplementary Cu and reduced by Cu chelation. Molecular modeling predicts 3 Cu and cDDP binding sites and quantum chemistry calculations indicate that cDDP would be expected to displace Cu from each of these sites. We conclude that, at clinically relevant concentrations, cDDP binds to and inhibits MEK1/2 and that both the binding and inhibitory activity are related to its interaction with Cu bound to MEK1/2. This may provide the basis for useful interactions of cDDP with other drugs that inhibit MAPK pathway signaling.

The description of aggregation processes with molecular dynamics simulations is a playground for testing biomolecular force fields, including a new generation of force fields that explicitly describe electronic polarization. In this work, we study a system consisting of 50 glycyl-l-alanine (Gly-Ala) dipeptides in solution with 1001 water molecules. Neutron diffraction experiments have shown that at this concentration, Gly-Ala aggregates into large clusters. However, general-purpose force fields in combination with established water models can fail to correctly describe this aggregation process, highlighting important deficiencies in how solute-solute and solute-solvent interactions are parametrized in these force fields. We found that even for the fully polarizable AMOEBA force field, the degree of association is considerably underestimated. Instead, a fixed point-charge approach based on the newly developed IPolQ scheme [Cerutti et al. J. Phys. Chem.2013, 117, 2328] allows for the correct modeling of the dipeptide aggregation in aqueous solution. This result should stimulate interest in novel fitting schemes that aim to improve the description of the solvent polarization effect within both explicitly polarizable and fixed point-charge frameworks.

Background: Trabeculae in vertebral bodies are unequally distributed within the cervical spine (CS), the thoracic spine (TS), and lumbar spine (LS). Such structures are also unequally distributed within the individual vertebrae. Exact knowledge of the microstructure of these entities could impact our understanding and treatment of fractures caused by osteoporosis and possibly improve surgical approaches. Appropriate investigations could help clarify the pathomechanisms of different forms of osteoporotic vertebral fractures, as well as different changes in morphological findings like the trabecular bone score (TBS). In the present study, we applied punctures to the craniocaudal and ventrocaudal directions and obtained cylinders of cancellous bone from the central portions and marginal regions of cervical vertebrae 5 and 6, thoracic vertebrae 8 and 12, and lumbar vertebrae 1 and 3. We systematically analyzed these samples to determine the bone volume fraction, trabecular thickness, separation, connectivity density, degree of anisotropy, and structure model index. Methods: Using an 8-gauge Jamshidi needle, we obtained samples from three quadrants (Q I: right margin; Q II: central; Q III: left margin) in the frontal and transverse plane and prepared these samples with a moist cloth in a 1.5 mL Eppendorf reaction vessel. The investigations were performed on a micro-CT device (SKYSCAN 1172, RJL Micro & Analytic Company, Karlsdorf-Neuthard, Germany). All collected data were analyzed using the statistical software package SPSS (version 24.0, IBM Corp., Armonk, NY, USA). Student's t test, the Wilcoxon–Mann–Whitney test, the Chi-squared test, and univariate analysis were used for between-group comparisons. The selection of the test depended on the number of investigated groups and the result of the Shapiro–Wilk test of normal distribution. In the case of statistically significant results, a post hoc LSD test was performed. Results: In total, we obtained 360 bone samples from 20 body donors. The craniocaudal puncture yielded data of similar magnitudes for all investigated parameters in all three quadrants, with the highest values observed in the CS. Comparisons of the ventrodorsal and craniocaudal microstructure revealed a significantly lower trabecular density and a significantly higher degree of anisotropy in the craniocaudal direction. Conclusions: The results presented different distributions and behaviors of trabecular density, with lower density in the mid-vertebral region over the entire breadth of the vertebrae. Reduced trabecular density caused a higher degree of anisotropy and was, therefore, associated with a lower capacity to sustain biomechanical loads. Fractures in fish vertebrae were easily explained by this phenomenon. The different changes in these structures could be responsible, in part, for the changes in the TBS determined using dual-energy X-ray absorptiometry. These results confirm the clinical relevance of the TBS. [ABSTRACT FROM AUTHOR]

Many-body potential energy functions (MB-PEFs), which integrate data-driven representations of many-body short-range quantum mechanical interactions with physics-based representations of many-body polarization and long-range interactions, have recently been shown to provide high accuracy in the description of molecular interactions from the gas to the condensed phase. Here, we present MB-Fit, a software infrastructure for the automated development of MB-PEFs for generic molecules within the TTM-nrg (Thole-type model energy) and MB-nrg (many-body energy) theoretical frameworks. Besides providing all the necessary computational tools for generating TTM-nrg and MB-nrg PEFs, MB-Fit provides a seamless interface with the MBX software, a many-body energy and force calculator for computer simulations. Given the demonstrated accuracy of the MB-PEFs, particularly within the MB-nrg framework, we believe that MB-Fit will enable routine predictive computer simulations of generic (small) molecules in the gas, liquid, and solid phases, including, but not limited to, the modeling of quantum isomeric equilibria in molecular clusters, solvation processes, molecular crystals, and phase diagrams. [ABSTRACT FROM AUTHOR]