Shape variation in protein binding pockets and their ligands

A common assumption about the shape of protein binding pockets is that they are related to the shape of the small ligand molecules that can bind there. But to what extent is that assumption true? Here we use a recently developed shape matching method to compare the shapes of protein binding pockets to the shapes of their ligands. We find that pockets binding the same ligand show greater variation in their shapes than can be accounted for by the conformational variability of the ligand. This suggests that geometrical complementarity in general is not sufficient to drive molecular recognition. Nevertheless, we show when considering only shape and size that a significant proportion of the recognition power of a binding pocket for its ligand resides in its shape. Additionally, we observe a "buffer zone" or a region of free space between the ligand and protein, which results in binding pockets being on average three times larger than the ligand that they bind.     

Addressing the intrinsic disorder bottleneck in structural proteomics

The Center for Eukaryotic Structural Genomics (CESG), as part of the Protein Structure Initiative (PSI), has established a high-throughput structure determination pipeline focused on eukaryotic proteins. NMR spectroscopy is an integral part of this pipeline, both as a method for structure determinations and as a means for screening proteins for stable structure. Because computational approaches have estimated that many eukaryotic proteins are highly disordered, about 1 year into the project, CESG began to use an algorithm (the Predictor of Naturally Disordered Regions, PONDR to avoid proteins that were likely to be disordered. We report a retrospective analysis of the effect of this filtering on the yield of viable structure determination candidates. In addition, we have used our current database of results on 70 protein targets from Arabidopsis thaliana and 1 from Caenorhabditis elegans, which were labeled uniformly with nitrogen-15 and screened for disorder by NMR spectroscopy, to compare the original algorithm with 13 other approaches for predicting disorder from sequence. Our study indicates that the efficiency of structural proteomics of eukaryotes can be improved significantly by removing targets predicted to be disordered by an algorithm chosen to provide optimal performance.     

Sexual selection research on spiders: progress and biases

The renaissance of interest in sexual selection during the last decades has fuelled an extraordinary increase of scientific papers on the subject in spiders. Research has focused both on the process of sexual selection itself, for example on the signals and various modalities involved, and on the patterns, that is the outcome of mate choice and competition depending on certain parameters. Sexual selection has most clearly been demonstrated in cases involving visual and acoustical signals but most spiders are myopic and mute, relying rather on vibrations, chemical and tactile stimuli. This review argues that research has been biased towards modalities that are relatively easily accessible to the human observer. Circumstantial and comparative evidence indicates that sexual selection working via substrate-borne vibrations and tactile as well as chemical stimuli may be common and widespread in spiders. Pattern-oriented research has focused on several phenomena for which spiders offer excellent model objects, like sexual size dimorphism, nuptial feeding, sexual cannibalism, and sperm competition. The accumulating evidence argues for a highly complex set of explanations for seemingly uniform patterns like size dimorphism and sexual cannibalism. Sexual selection appears involved as well as natural selection and mechanisms that are adaptive in other contexts only. Sperm competition has resulted in a plethora of morphological and behavioural adaptations, and simplistic models like those linking reproductive morphology with behaviour and sperm priority patterns in a straightforward way are being replaced by complex models involving an array of parameters. Male mating costs are increasingly being documented in spiders, and sexual selection by male mate choice is discussed as a potential result. Research on sexual selection in spiders has come a long way since Darwin, whose spider examples are reanalysed in the context of contemporary knowledge, but the same biases and methodological constraints have persisted almost unchanged through the current boom of research.     

Responses of domestic chicks (Gallus gallus domesticus) to multimodal aposematic signals

Many aposematic prey combine their visual warning signals withadditional signals. Together, these signals constitute a multimodalor multicomponent warning display. The additional signals arethought to increase the effects of the visual signals on predators.Olfactory signals are much emphasized, but later studies haveshown that also auditory signals like the buzzing of certaininsects might have multimodal effects. The wasp displays typicalvisual aposematic signals, black and yellow stripes, but doesalso emit a characteristic buzzing. We wanted to test if, andin what way, the visual and acoustic display of the wasp hasan aversive function on the predators. We therefore conducteda 12-trial discrimination-learning task on inexperienced chicksto study whether there are innate biases toward these signalsand how they affect the speed of avoidance learning. We alsoperformed three extinction-learning trials to study how memorablethe signals were to the chicks. We show that the visual signalsin the display of the wasp contribute to the protection frompredators but in different ways; the yellow color had an aversiveeffect on inexperienced predators, while the striped patternimproved the aversion learning. The sound did not enhance theinnate aversions but increased the aversion learning of stripesin green prey.     

Uncinaria stenocephala: assessment of antigens for the immunodiagnosis of canine uncinariosis

Although Uncinaria stenocephala is the most frequent hookworm in the intestine of dogs from Northern, Central and Southern Europe, little is known about its host-parasite relationship. Three groups of sera from dogs (Group 1: dogs naturally infected only by U. stenocephala; Group 2: helminth-free dogs at necropsy, and Group 3: dogs parasitized by other helminths) were analyzed by ELISA using U. stenocephala antigens from adult worms (somatic and excretory-secretory antigens) and from L3 larvae (somatic antigens). All three sources of antigens were found to be suitable for immunodiagnosis of canine uncinariosis with up to 90% efficacy. However, an analysis to assess the diagnostic value of the different antigens demonstrated that the adult excretory-secretory antigens had a higher diagnostic efficacy (96.7%), indicating that this is the best antigen source for the diagnosis of Uncinaria infection.     

Propagule vs. niche limitation: untangling the mechanisms behind plant species' distributions

Distinguishing the roles of propagule limitation and niche requirements in controlling plant species distributions is important for understanding community structure, invasion, and restoration. We used species distribution models based on plant and environmental survey data to assess the strength of species' affinities for particular environmental conditions. We hypothesized that species with statistically detectable environmental requirements were primarily niche-limited, while species with weak habitat affinities were primarily propagule-limited. We tested this hypothesis via a seeding experiment in which we compared species' reproductive fitness in occupied and unoccupied sites. Species that appeared to be niche-limited based on distribution models had lower fitness when planted in unoccupied sites, while species that models suggested were propagule-limited had equivalent fitness when planted in occupied and unoccupied sites. Our results demonstrate that within a single community, both species limited primarily by niche availability or primarily by propagule availability can be identified using observational data.     

Comparative psychology and the grand challenge of drug discovery in psychiatry and neurodegeneration

Drug discovery for brain disorders is undergoing a period of upheaval. Faced with an empty drug pipeline and numerous failures of potential new drugs in clinical trials, many large pharmaceutical companies have been shrinking or even closing down their research divisions that focus on central nervous system (CNS) disorders. In this paper, we argue that many of the difficulties facing CNS drug discovery stem from a lack of robustness in pre-clinical (i.e., non-human animal) testing. There are two main sources for this lack of robustness. First, there is the lack of replicability of many results from the pre-clinical stage, which we argue is driven by a combination of publication bias and inappropriate selection of statistical and experimental designs. Second, there is the frequent failure to translate results in non-human animals to parallel results in humans in the clinic. This limitation can only be overcome by developing new behavioral tests for non-human animals that have predictive, construct, and etiological validity. Here, we present these translational difficulties as a “grand challenge” to researchers from comparative cognition, who are well positioned to provide new methods for testing behavior and cognition in non-human animals. These new experimental protocols will need to be both statistically robust and target behavioral and cognitive processes that allow for better connection with human CNS disorders. Our hope is that this downturn in industrial research may represent an opportunity to develop new protocols that will re-kindle the search for more effective and safer drugs for CNS disorders.