PocketGraph : graph representation of binding site volumes

The representation of small molecules as molecular graphs is a common technique in various fields of cheminformatics. This approach employs abstract descriptions of topology and properties for rapid analyses and comparison. Receptor-based methods in contrast mostly depend on more complex representations impeding simplified analysis and limiting the possibilities of property assignment. In this study we demonstrate that ligand-based methods can be applied to receptor-derived binding site analysis. We introduce the new method PocketGraph that translates representations of binding site volumes into linear graphs and enables the application of graph-based methods to the world of protein pockets. The method uses the PocketPicker algorithm for characterization of binding site volumes and employs a Growing Neural Gas procedure to derive graph representations of pocket topologies. Self-organizing map (SOM) projections revealed a limited number of pocket topologies. We argue that there is only a small set of pocket shapes realized in the known ligand-receptor complexes

Negative and positive externalities in intergroup conflict: exposure to the opportunity to help the outgroup reduces the inclination to harm it

Outgroup hate, in the context of intergroup conflict, can be expressed by harming the outgroup, but also by denying it help. Previous work established that this distinction—whether the externality on the outgroup is negative or positive—has an important effect on the likelihood of outgroup hate emerging as a motivation for individual participation in intergroup conflict. The current work uses a within-subject design to examine the behavior of the same individuals in intergroup conflict with negative and positive externalities on the outgroup. Each participant made two choices, one for each type of externality, and the order was counter balanced. The main results are that (1) behavior is fairly consistent across negative and positive externalities, i.e., the tendency to display outgroup hate by harming the outgroup is correlated with the tendency to display outgroup hate by avoiding to help the outgroup; (2) People are reluctant to harm the outgroup after being exposed to the opportunity to help it; (3) Groupness—the degree to which people care about their group and its well-being—is related to outgroup hate only when participants encounter the opportunity to harm the outgroup first (before they encounter the opportunity to help it). In this setting the relationship between groupness and outgroup hate spilled over to the subsequent interaction, where it was possible to help the outgroup. When the opportunity to help the outgroup was encountered first, groupness was not related to outgroup hate

Fuzzy virtual ligands for virtual screening

A new method to bridge the gap between ligand and receptor-based methods in virtual screening (VS) is presented. We introduce a structure-derived virtual ligand (VL) model as an extension to a previously published pseudo-ligand technique [1]: LIQUID [2] fuzzy pharmacophore virtual screening is combined with grid-based protein binding site predictions of PocketPicker [3]. This approach might help reduce bias introduced by manual selection of binding site residues and introduces pocket shape information to the VL. It allows for a combination of several protein structure models into a single "fuzzy" VL representation, which can be used to scan screening compound collections for ligand structures with a similar potential pharmacophore. PocketPicker employs an elaborate grid-based scanning procedure to determine buried cavities and depressions on the protein's surface. Potential binding sites are represented by clusters of grid probes characterizing the shape and accessibility of a cavity. A rule-based system is then applied to project reverse pharmacophore types onto the grid probes of a selected pocket. The pocket pharmacophore types are assigned depending on the properties and geometry of the protein residues surrounding the pocket with regard to their relative position towards the grid probes. LIQUID is used to cluster representative pocket probes by their pharmacophore types describing a fuzzy VL model. The VL is encoded in a correlation vector, which can then be compared to a database of pre-calculated ligand models. A retrospective screening using the fuzzy VL and several protein structures was evaluated by ten fold cross-validation with ROC-AUC and BEDROC metrics, obtaining a significant enrichment of actives. Future work will be devoted to prospective screening using a novel protein target of Helicobacter pylori and compounds from commercial providers

Support for Same-Sex Marriage at Record High, but Key Segments Remain Opposed

As the Supreme Court prepares to decide a key case involving states' requirements to recognize same-sex marriage, public support for allowing gays and lesbians to marry legally continues its rapid rise: A 57%-majority of Americans now favor allowing same-sex marriage and 39% oppose. As recently as five years ago, more opposed (48%) same-sex marriage than supported it (42%).This is the highest level of support measured for same-sex marriage in nearly 20 years of Pew Research Center polling of the issue. Yet even as support for same-sex marriage has increased among nearly all segments in the public, some groups remain broadly opposed to gay marriage.The Pew Research Center survey, conducted May 12-18 among 2,002 adults, finds that partisans are as divided on this issue as ever: Today, 65% of Democrats and an identical percentage of independents favor gay marriage; only about one third (34%) of Republicans do so. Growing shares of all three groups support same-sex-marriage, yet the differences between Democrats and Republicans are as wide today as they were a decade ago

PocketPicker: analysis of ligand binding-sites with shape descriptors

Background Identification and evaluation of surface binding-pockets and occluded cavities are initial steps in protein structure-based drug design. Characterizing the active site's shape as well as the distribution of surrounding residues plays an important role for a variety of applications such as automated ligand docking or in situ modeling. Comparing the shape similarity of binding site geometries of related proteins provides further insights into the mechanisms of ligand binding. Results We present PocketPicker, an automated grid-based technique for the prediction of protein binding pockets that specifies the shape of a potential binding-site with regard to its buriedness. The method was applied to a representative set of protein-ligand complexes and their corresponding apo-protein structures to evaluate the quality of binding-site predictions. The performance of the pocket detection routine was compared to results achieved with the existing methods CAST, LIGSITE, LIGSITEcs, PASS and SURFNET. Success rates PocketPicker were comparable to those of LIGSITEcs and outperformed the other tools. We introduce a descriptor that translates the arrangement of grid points delineating a detected binding-site into a correlation vector. We show that this shape descriptor is suited for comparative analyses of similar binding-site geometry by examining induced-fit phenomena in aldose reductase. This new method uses information derived from calculations of the buriedness of potential binding-sites. Conclusions The pocket prediction routine of PocketPicker is a useful tool for identification of potential protein binding-pockets. It produces a convenient representation of binding-site shapes including an intuitive description of their accessibility. The shape-descriptor for automated classification of binding-site geometries can be used as an additional tool complementing elaborate manual inspections

Mechanical Stability and Fibrinolytic Resistance of Clots Containing Fibrin, DNA, and Histones

Neutrophil extracellular traps are networks of DNA and associated proteins produced by nucleosome release from activated neutrophils in response to infection stimuli and have recently been identified as key mediators between innate immunity, inflammation, and hemostasis. The interaction of DNA and histones with a number of hemostatic factors has been shown to promote clotting and is associated with increased thrombosis, but little is known about the effects of DNA and histones on the regulation of fibrin stability and fibrinolysis. Here we demonstrate that the addition of histone-DNA complexes to fibrin results in thicker fibers (increase in median diameter from 84 to 123 nm according to scanning electron microscopy data) accompanied by improved stability and rigidity (the critical shear stress causing loss of fibrin viscosity increases from 150 to 376 Pa whereas the storage modulus of the gel increases from 62 to 82 pascals according to oscillation rheometric data). The effects of DNA and histones alone are subtle and suggest that histones affect clot structure whereas DNA changes the way clots are lysed. The combination of histones + DNA significantly prolongs clot lysis. Isothermal titration and confocal microscopy studies suggest that histones and DNA bind large fibrin degradation products with 191 and 136 nm dissociation constants, respectively, interactions that inhibit clot lysis. Heparin, which is known to interfere with the formation of neutrophil extracellular traps, appears to prolong lysis time at a concentration favoring ternary histone-DNA-heparin complex formation, and DNase effectively promotes clot lysis in combination with tissue plasminogen activator

Foam-like compression behavior of fibrin networks

The rheological properties of fibrin networks have been of long-standing interest. As such there is a wealth of studies of their shear and tensile responses, but their compressive behavior remains unexplored. Here, by characterization of the network structure with synchronous measurement of the fibrin storage and loss moduli at increasing degrees of compression, we show that the compressive behavior of fibrin networks is similar to that of cellular solids. A non-linear stress-strain response of fibrin consists of three regimes: 1) an initial linear regime, in which most fibers are straight, 2) a plateau regime, in which more and more fibers buckle and collapse, and 3) a markedly non-linear regime, in which network densification occurs {{by bending of buckled fibers}} and inter-fiber contacts. Importantly, the spatially non-uniform network deformation included formation of a moving "compression front" along the axis of strain, which segregated the fibrin network into compartments with different fiber densities and structure. The Young's modulus of the linear phase depends quadratically on the fibrin volume fraction while that in the densified phase depends cubically on it. The viscoelastic plateau regime corresponds to a mixture of these two phases in which the fractions of the two phases change during compression. We model this regime using a continuum theory of phase transitions and analytically predict the storage and loss moduli which are in good agreement with the experimental data. Our work shows that fibrin networks are a member of a broad class of natural cellular materials which includes cancellous bone, wood and cork

Social motives in intergroup conflict

We experimentally test the social motives behind individual participation in intergroup conflict by manipulating the framing and symmetry of conflict. We find that behavior in conflict depends on whether one is harmed by actions perpetrated by the out-group, but not on one's own influence on the outcome of the out-group. The way in which this harm is presented and perceived dramatically alters participation decisions. When people perceive their group to be under threat, they are mobilized to do what is good for the group and contribute to the conflict. On the other hand, if people perceive to be personally under threat, they are driven to do what is good for themselves and withhold their contribution. The first phenomenon is attributed to group identity, possibly combined with a concern for social welfare. The second phenomenon is attributed to a novel victim effect. Another social motive - reciprocity - is ruled out by the data

Quantitative structural mechanobiology of platelet-driven blood clot contraction.

Blood clot contraction plays an important role in prevention of bleeding and in thrombotic disorders. Here, we unveil and quantify the structural mechanisms of clot contraction at the level of single platelets. A key elementary step of contraction is sequential extension-retraction of platelet filopodia attached to fibrin fibers. In contrast to other cell-matrix systems in which cells migrate along fibers, the "hand-over-hand" longitudinal pulling causes shortening and bending of platelet-attached fibers, resulting in formation of fiber kinks. When attached to multiple fibers, platelets densify the fibrin network by pulling on fibers transversely to their longitudinal axes. Single platelets and aggregates use actomyosin contractile machinery and integrin-mediated adhesion to remodel the extracellular matrix, inducing compaction of fibrin into bundled agglomerates tightly associated with activated platelets. The revealed platelet-driven mechanisms of blood clot contraction demonstrate an important new biological application of cell motility principles