Polyelectrolyte interactions enable rapid association and dissociation in high-affinity disordered protein complexes

Highly charged intrinsically disordered proteins can form complexes with very high affinity in which both binding partners fully retain their disorder and dynamics, exemplified by the positively charged linker histone H1.0 and its chaperone, the negatively charged prothymosin α. Their interaction exhibits another surprising feature: The association/dissociation kinetics switch from slow two-state-like exchange at low protein concentrations to fast exchange at higher, physiologically relevant concentrations. Here we show that this change in mechanism can be explained by the formation of transient ternary complexes favored at high protein concentrations that accelerate the exchange between bound and unbound populations by orders of magnitude. Molecular simulations show how the extreme disorder in such polyelectrolyte complexes facilitates (i) diffusion-limited binding, (ii) transient ternary complex formation, and (iii) fast exchange of monomers by competitive substitution, which together enable rapid kinetics. Biological polyelectrolytes thus have the potential to keep regulatory networks highly responsive even for interactions with extremely high affinities

Empirical Optimization of Interactions between Proteins and Chemical Denaturants in Molecular Simulations

Chemical denaturants are the most commonly used perturbation applied to study protein stability and folding kinetics as well as the properties of unfolded polypeptides. We build on recent work balancing the interactions of proteins and water, and accurate models for the solution properties of urea and guanidinium chloride, to develop a combined force field that is able to capture the strength of interactions between proteins and denaturants. We use solubility data for a model tetraglycine peptide in each denaturant to tune the protein-denaturant interaction by a novel simulation methodology. We validate the results against data for more complex sequences: single-molecule Förster resonance energy transfer data for a 34-residue fragment of the globular protein CspTm and photoinduced electron transfer quenching data for the disordered peptides C(AGQ)nW in denaturant solution as well as the chemical denaturation of the mini-protein Trp cage. The combined force field model should aid our understanding of denaturation mechanisms and the interpretation of experiment

The growth and erosion of cinder cones in Guatemala and El Salvador: Models and statistics

Morphologic data for 147 cinder cones in southern Guatemala andwestern El Salvador are comparedwith data from the San Francisco volcanic field, Arizona (USA), Cima volcanic field, California (USA), Michoácan–Guanajuato volcanic field, Mexico, and the Lamongan volcanic field, East Java. The Guatemala cones have an average height of 110+/-50 m, an average basal diameter of 660+/-230 m and an average top diameter of 180+/-150 m. The generalmorphology of these cones can be described by their average cone angle of slope (24+/-7), average heightto- radius ratio (0.33+/-0.09) and their flatness (0.24+/-0.18). Although the mean values for the Guatemalan cones are similar to those for other volcanic fields (e.g., San Francisco volcanic field, Arizona; Cima volcanic field, California; Michoácan–Guanajuato volcanic field, Mexico; and Lamongan volcanic field, East Java), the range of morphologies encompasses almost all of those observed worldwide for cinder cones. Three new 40Ar/39Ar age dates are combined with 19 previously published dates for cones in Guatemala and El Salvador. There is no indication that the morphologies of these cones have changed over the last 500–1000 ka. Furthermore, a re-analysis of published data for other volcanic fields suggests that only in the Cima volcanic field (of those studied) is there clear evidence of degradation with age. Preliminary results of a numerical model of cinder cone growth are used to show that the range of morphologies observed in the Guatemalan cinder cones could all be primary, that is, due to processes occurring at the time of eruption

The growth and erosion of cinder cones in Guatemala and El Salvador: Models and statistics

Morphologic data for 147 cinder cones in southern Guatemala andwestern El Salvador are comparedwith data from the San Francisco volcanic field, Arizona (USA), Cima volcanic field, California (USA), Michoácan–Guanajuato volcanic field, Mexico, and the Lamongan volcanic field, East Java. The Guatemala cones have an average height of 110+/-50 m, an average basal diameter of 660+/-230 m and an average top diameter of 180+/-150 m. The generalmorphology of these cones can be described by their average cone angle of slope (24+/-7), average heightto- radius ratio (0.33+/-0.09) and their flatness (0.24+/-0.18). Although the mean values for the Guatemalan cones are similar to those for other volcanic fields (e.g., San Francisco volcanic field, Arizona; Cima volcanic field, California; Michoácan–Guanajuato volcanic field, Mexico; and Lamongan volcanic field, East Java), the range of morphologies encompasses almost all of those observed worldwide for cinder cones. Three new 40Ar/39Ar age dates are combined with 19 previously published dates for cones in Guatemala and El Salvador. There is no indication that the morphologies of these cones have changed over the last 500–1000 ka. Furthermore, a re-analysis of published data for other volcanic fields suggests that only in the Cima volcanic field (of those studied) is there clear evidence of degradation with age. Preliminary results of a numerical model of cinder cone growth are used to show that the range of morphologies observed in the Guatemalan cinder cones could all be primary, that is, due to processes occurring at the time of eruption

One-Liners

One-Liners from P.T. Borgia, J. Irelan and E.U. Selker, and B.C. Turner and A. Fairfiel

Screening for hotspot mutations in PI3K, JAK2, FLT3 and NPM1 in patients with myelodysplastic syndromes

INTRODUCTION: Myelodysplastic syndromes encompass a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, refractory cytopenia and a tendency to progress toward acute myeloid leukemia. The accumulation of genetic alterations is closely associated with the progression of myelodysplastic syndromes toward acute myeloid leukemia. OBJECTIVE: To investigate the presence of mutations in the points most frequent for mutations (hotspot mutations) in phosphatidylinositol-3-kinase (PI3K), Janus kinase 2 (JAK2), FMS-like tyrosine kinase 3 (FLT3) and nucleophosmin (NPM1), which are involved in leukemia and other cancers, in a population of Brazilian MDS patients. METHODS: Fifty-one myelodysplastic syndromes patients were included in the study. According to French-American-British classification, the patients were distributed as follows: 31 with refractory anemia, 8 with refractory anemia with ringed sideroblasts, 7 with refractory anemia with excess blasts, 3 with refractory anemia with excess blasts in transformation and 2 with chronic myelomonocytic leukemia. Bone marrow samples were obtained and screened for the presence of hotspot mutations using analysis based on amplification with the polymerase chain reaction, sequencing, fragment size polymorphisms or restriction enzyme digestion. All patients were screened for mutations at the time of diagnosis, and 5 patients were also screened at the time of disease progression. RESULTS: In the genes studied, no mutations were detected in the patients at the time of diagnosis. One patient with chronic myelomonocytic leukemia was heterozygous for a Janus kinase 2 mutation after disease progression. CONCLUSIONS: These results show that hotspot mutations in the PI3K, JAK2, FLT3 and NPM1 genes are not common in MDS patients; nevertheless, JAK2 mutations may be present in myelodysplasia during disease progression

Creativity and Autonomy in Swarm Intelligence Systems

This work introduces two swarm intelligence algorithms -- one mimicking the behaviour of one species of ants (\emph{Leptothorax acervorum}) foraging (a `Stochastic Diffusion Search', SDS) and the other algorithm mimicking the behaviour of birds flocking (a `Particle Swarm Optimiser', PSO) -- and outlines a novel integration strategy exploiting the local search properties of the PSO with global SDS behaviour. The resulting hybrid algorithm is used to sketch novel drawings of an input image, exploliting an artistic tension between the local behaviour of the `birds flocking' - as they seek to follow the input sketch - and the global behaviour of the `ants foraging' - as they seek to encourage the flock to explore novel regions of the canvas. The paper concludes by exploring the putative `creativity' of this hybrid swarm system in the philosophical light of the `rhizome' and Deleuze's well known `Orchid and Wasp' metaphor