Learning Protein-Ligand Unbinding Pathways via Single-Parameter Community Detection.

Understanding the dynamics of biomolecular complexes, e.g., of protein-ligand (un)binding, requires the comprehension of paths such systems take between metastable states. In MD simulations, paths are usually not observable per se, but they need to be inferred from simulation trajectories. Here, we present a novel approach to cluster trajectories based on a community detection algorithm that necessitates only the definition of a single parameter. The unbinding of the streptavidin-biotin complex is used as a benchmark system and the A2a adenosine receptor in complex with the inhibitor ZM241385 as an elaborate application. We demonstrate how such clusters of trajectories correspond to pathways and how the approach helps in the identification of reaction coordinates for a considered (un)binding process.

[Five past twelve - the resistance situation in small ruminant gastrointestinal nematodes in Germany]. / Fünf nach zwölf ­ zur Resistenzlage gastrointestinaler Nematoden bei kleinen Wiederkäuern in Deutschland.

Anthelmintic resistance has reached alarming levels worldwide and already seriously threatens pasture-based small ruminant production in certain geographic regions. The situation in Europe has also dramatically deteriorated in the last decade. This review provides an overview of the occurrence of anthelmintic resistance in small ruminants with a particular focus on Germany and its neighbouring countries. It also covers mechanisms leading to the development and spread of anthelmintic resistance, and recommendations for a responsible use of anthelmintics in veterinary practice.

Anisotropic Friction in a Ligand-Protein Complex.

The effect of an externally applied directional force on molecular friction is so far poorly understood. Here, we study the force-driven dissociation of the ligand-protein complex biotin-streptavidin and identify anisotropic friction as a not yet described type of molecular friction. Using AFM-based stereographic single molecule force spectroscopy and targeted molecular dynamics simulations, we find that the rupture force and friction for biotin-streptavidin vary with the pulling angle. This observation holds true for friction extracted from Kramers' rate expression and by dissipation-corrected targeted molecular dynamics simulations based on Jarzynski's identity. We rule out ligand solvation and protein-internal friction as sources of the angle-dependent friction. Instead, we observe a heterogeneity in free energy barriers along an experimentally uncontrolled orientation parameter, which increases the rupture force variance and therefore the overall friction. We anticipate that anisotropic friction needs to be accounted for in a complete understanding of friction in biomolecular dynamics and anisotropic mechanical environments.

Effectiveness of Anthelmintic Treatments in Small Ruminants in Germany.

Widespread anthelmintic resistance is a concern for small ruminant health and production worldwide. The current situation regarding anthelmintic efficacy is, however, not very well studied in Germany. Thus, a nationwide field study was undertaken to assess the effectiveness of 253 treatments performed in 223 small ruminant flocks by faecal egg count reduction test (FECRT) using pooled samples and a modified McMaster method. The percentage of Haemonchus contortus and non-Haemonchus eggs was determined by fluorescence microscopy following peanut agglutinin-fluorescein isothiocyanate staining. Treatments were chosen and performed by farmers together with their local veterinarian, and potentially confounding factors for FECRT results were addressed as far as possible by rigorous inclusion criteria. Reduced effectiveness was observed for treatments with all examined anthelmintic classes, but treatments with benzimidazoles and moxidectin showed significantly poorer results than monepantel, a closantel and mebendazole combination, and levamisole. Low case numbers precluded reliable assessment of avermectins. Unsuccessful treatments were frequently associated with the survival of H. contortus, but this was also observed for non-Haemonchus genera. The results are highly concerning, and sustainable approaches to parasite control are urgently needed to prevent further deterioration of this situation.

Rumen and Liver Fluke Infections in Sheep and Goats in Northern and Southern Germany.

Paramphistomidosis has recently been identified as an emerging parasitosis in Europe. This study estimated the prevalence of rumen flukes, Fasciola hepatica and Dicrocoelium dendriticum, in small ruminants in Germany and identified occurring rumen fluke species and potential predictors for fluke infections. Pooled fecal samples from 223 sheep farms and 143 goat farms in northern and southern Germany were examined by the sedimentation technique, and molecular species identification was performed on rumen-fluke-positive samples. In sheep, a flock prevalence of 2.2% was detected for rumen flukes. Calicophoron daubneyi was identified on four of five positive farms, while species identification failed in one flock. No rumen fluke eggs were detected in the examined goat herds. F. hepatica eggs were detected in 2.7% of the sheep flocks, while the herd prevalence was 5.6% in goats. Higher prevalence values of 21.1% (sheep) and 7.0% (goats) were observed for D. dendriticum. Mixed grazing with other ruminants and previously identified infections with rumen flukes and/or F. hepatica were identified as predictors for paramphistomidosis. The distribution of the three trematode species followed a geographical pattern associated with conditions favoring the relevant intermediate hosts. C. daubneyi is an established parasite in German sheep at a currently low prevalence.

Predicting Ion Channel Conductance via Dissipation-Corrected Targeted Molecular Dynamics and Langevin Equation Simulations.

Ion channels are important proteins for physiological information transfer and functional control. To predict the microscopic origins of their voltage-conductance characteristics, here we applied dissipation-corrected targeted molecular dynamics in combination with Langevin equation simulations to potassium diffusion through the gramicidin A channel as a test system. Performing a nonequilibrium principal component analysis on backbone dihedral angles, we find coupled protein-ion dynamics to occur during ion transfer. The dissipation-corrected free energy profiles correspond well to predictions from other biased simulation methods. The incorporation of an external electric field in Langevin simulations enables the prediction of macroscopic observables in the form of I-V characteristics.