Functional Sites Induce Long-Range Evolutionary Constraints in Enzymes

Functional residues in proteins tend to be highly conserved over evolutionary time. However, to what extent functional sites impose evolutionary constraints on nearby or even more distant residues is not known. Here, we report pervasive conservation gradients toward catalytic residues in a dataset of 524 distinct enzymes: evolutionary conservation decreases approximately linearly with increasing distance to the nearest catalytic residue in the protein structure. This trend encompasses, on average, 80% of the residues in any enzyme, and it is independent of known structural constraints on protein evolution such as residue packing or solvent accessibility. Further, the trend exists in both monomeric and multimeric enzymes and irrespective of enzyme size and/or location of the active site in the enzyme structure. By contrast, sites in protein–protein interfaces, unlike catalytic residues, are only weakly conserved and induce only minor rate gradients. In aggregate, these observations show that functional sites, and in particular catalytic residues, induce long-range evolutionary constraints in enzymes.Fil: Jack, Benjamin R.. University of Texas at Austin; Estados UnidosFil: Meyer, Austin G.. University of Texas at Austin; Estados UnidosFil: Echave, Julián. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Wilke, Claus O.. University of Texas at Austin; Estados Unido

Analyzing Machupo virus-receptor binding by molecular dynamics simulations

In many biological applications, we would like to be able to computationally predict mutational effects on affinity in protein-protein interactions. However, many commonly used methods to predict these effects perform poorly in important test cases. In particular, the effects of multiple mutations, non-alanine substitutions, and flexible loops are difficult to predict with available tools and protocols. We present here an existing method applied in a novel way to a new test case; we interrogate affinity differences resulting from mutations in a host-virus protein-protein interface. We use steered molecular dynamics (SMD) to computationally pull the machupo virus (MACV) spike glycoprotein (GP1) away from the human transferrin receptor (hTfR1). We then approximate affinity using the maximum applied force of separation and the area under the force-versus-distance curve. We find, even without the rigor and planning required for free energy calculations, that these quantities can provide novel biophysical insight into the GP1/hTfR1 interaction. First, with no prior knowledge of the system we can differentiate among wild type and mutant complexes. Moreover, we show that this simple SMD scheme correlates well with relative free energy differences computed via free energy perturbation. Second, although the static co-crystal structure shows two large hydrogen-bonding networks in the GP1/hTfR1 interface, our simulations indicate that one of them may not be important for tight binding. Third, one viral site known to be critical for infection may mark an important evolutionary suppressor site for infection-resistant hTfR1 mutants. Finally, our approach provides a framework to compare the effects of multiple mutations, individually and jointly, on protein-protein interactions.Comment: 33 pages, 8 figures, 5 table

Molecular methods for genomic analyses of variant PML-RARA or other RARA-related chromosomal translocations in acute promyelocytic leukemia

TO THE EDITOR: We read an interesting paper by Palta et al. in a recent issue of the Korean Journal of Hematology titled, "ZBTB16-RARA variant of acute promyelocytic leukemia with tuberculosis: a case report and review of literature" [1]. We would like to add some comments to their article and suggest additional molecular methods to confirm variant translocations in acute promyelocytic leukemia (APL)...

Spin-dependent electronic hybridization in a rope of carbon nanotubes

We demonstrate single electron addition to different strands of a carbon nanotube rope. Anticrossings of anomalous conductance peaks occur in quantum transport measurements through the parallel quantum dots forming on the individual strands. We determine the magnitude and the sign of the hybridization as well as the Coulomb interaction between the carbon nanotube quantum dots, finding that the bonding states dominate the transport. In a magnetic field the hybridization is shown to be selectively suppressed due to spin effects.Comment: 4 pages, 4 figure

DMAIC in Lithium-Ion-Battery Production

DMAIC refers to a data-driven cycle of analysis steps used for improving, optimizing and stabilizing business processes with the steps Define, Measure, Analyze, Improve, and Control (DMAIC). In this paper, we will demonstrate the Define, Measure, and Analyze steps for the calendering step in Lithium-Ion-Battery Production. It appears that the measurement system is at least questionable. Moreover, we identified influential factors for thickness and porosity of the foil

Impact of tunnel barrier strength on magnetoresistance in carbon nanotubes

We investigate magnetoresistance in spin valves involving CoPd-contacted carbon nanotubes. Both temperature and bias voltage dependence clearly indicate tunneling magnetoresistance as the origin. We show that this effect is significantly affected by the tunnel barrier strength, which appears to be one reason for the variation between devices previously detected in similar structures. Modeling the data by means of the scattering matrix approach, we find a non-trivial dependence of the magnetoresistance on the barrier strength. Furthermore, analysis of the spin precession observed in a nonlocal Hanle measurement yields a spin lifetime of $\tau_s = 1.1\,$ns, a value comparable with those found in silicon- or graphene-based spin valve devices.Comment: 10 pages, 5 figures, 1 tabl

Perseverative Thinking in Depression and Anxiety

The current study investigated the impact of worry and brooding as moderators of the tripartite model of depression and anxiety (TMDA). We hypothesized that both types of perseverative thinking would moderate the association between negative affectivity (NA) and both anxiety and depression. Complete data sets for this questionnaire survey were obtained from 537 students. Participants’ ages ranged from 16 to 49 years with a mean age of 21.1 years (SD = 3.6). Overall, results from path analyses supported the assumptions of the TMDA, in that NA was a non-specific predictor for both depression and anxiety whilst lack of positive affectivity (PA) was related to depression only. Unexpectedly, perseverative thinking had an effect on the dependency of negative and positive affectivity. Worry was a significant moderator for the path NA–anxiety. All other hypothesized associations were only marginally significant. Alternative pathways as well as methodological implications regarding similarities and differences of the two types of perseverative thinking are discussed

Different Carotenoids and Potential Information Content of Red Coloration of Male Three-Spined Stickleback

Female sticklebacks (Gasterosteus aculeatus) use the red coloration of males as a criterion for mate choice. Redder males are more attractive. However, males often differ not only in the intensity of their coloration (from dull to bright red) but also in color quality (from yellowish to purple-red). We investigated whether the red coloration of the stickleback is actually a multiple signal made by several pigments. We kept wild caught males singly in tanks until they had built a nest and were ready to accept females. Then, we took standard photographs and measured their colors by spectrometer analyses of the slides and by descriptions of human observers. These two measurements were highly correlated. When analyzing the carotenoid content of the sticklebacks' skin we found two groups of carotenoids (astaxanthin and tunaxanthin/lutein) that were quantified for each individual. The differences in color observed in the fish are correlated to this pigment quantification. Redder fish have more astaxanthin in their skin than yellowish fish, while the color of the yellowish fish appears to be made by tunaxanthin/lutein. Our results suggest that the red coloration of sticklebacks is a multiple trait that is made of at least two different carotenoids. This opens the possibility that male sticklebacks signal more detailed information to females than a one-dimensional trait would allo

Cutting Optimal Sections from Production Foils

Rechargeable Lithium-Ion battery cell production is one of the most important processes in the field of electro mobility. The batteries’ electrodes are produced in the form of long coated foils which are then cut into pieces of a predefined length called electrode sheets. The production process of the coated foils consists of several sequential process steps and quality parameters are measured frequently along the foil after each sub-process.We aim at determining the maximum number of electrode sheets that can be built from a produced foil of a certain length, with respect to given quality requirements. In a second step, we introduce an algorithm originated from the 0-1 multi-objective knapsack problem that is able to efficiently determine the optimal positions of the sheets based on all observed quality parameters