Exploring ligand stability in protein crystal structures using binding pose metadynamics

Identification of correct protein-ligand binding poses is important in structure-based drug design and crucial for the evaluation of protein-ligand binding affinity. Protein-ligand coordinates are commonly obtained from crystallography experiments that provide a static model of an ensemble of conformations. Binding pose metadynamics (BPMD) is an enhanced sampling method that allows for an efficient assessment of ligand stability in solution. Ligand poses that are unstable under the bias of the metadynamics simulation are expected to be infrequently occupied in the energy landscape, thus making minimal contributions to the binding affinity. Here, the robustness of the method is studied using crystal structures with ligands known to be incorrectly modeled, as well as 63 structurally diverse crystal structures with ligand fit to electron density from the Twilight database. Results show that BPMD can successfully differentiate compounds whose binding pose is not supported by the electron density from those with well-defined electron density

Leukocyte coping capacity as a complementary stress metric in migrating birds

Corticosterone (Cort) is involved in multiple physiological processes during bird migration, complicating its interpretation in a stress context. We investigated whether the leukocyte coping capacity (LCC) provides useful complementary information on the stress response in migratory Garden Warblers (Sylvia borin) and how it relates to Cort and energetic condition. Contrary to Cort levels, LCC significantly decreased, implying high-stress levels and a diminished capacity to recover after a stressful event. The absence of significant effects of body conditions on the stress parameters shows no simple relationship between these traits and highlights the need for additional stress metrics to measure stress in life-history contexts

Intra-sexual competition alters the relationship between testosterone and ornament expression in a wild territorial bird

Open Access funded by Natural Environment Research Council Under a Creative Commons licensePeer reviewedPublisher PD

Modulation by steroid hormones of a "sexy" acoustic signal in an Oscine species, the Common Canary Serinus canaria

The respective influence of testosterone and estradiol on the structure of the Common Canary Serinus canaria song was studied by experimentally controlling blood levels of steroid hormones in males and analyzing the consequent effects on acoustic parameters. A detailed acoustic analysis of the songs produced before and after hormonal manipulation revealed that testosterone and estradiol seem to control distinct song parameters independently. The presence of receptors for testosterone and estradiol in the brain neural pathway controlling song production strongly suggests that the observed effects are mediated by a steroid action at the neuronal level.<br>A influência da testosterona e do estradiol, respectivamente, na estrutura do canto do Canário-do-reino Serinus canaria foi estudada analisando o efeito da manipulação dos níveis sanguíneos de hormônios esteróides em machos nos parâmetros acústicos do canto. Uma analise detalhada dos cantos produzidos antes e depois da manipulação hormonal revelou que testosterona e estradiol parecem controlar independentemente parâmetros acústicos distintos. A presença de receptores para esses hormônios no circuito neuronal para controle da produção do canto sugere fortemente que os efeitos observados são mediados pela ação de esteróides a nivel neuronal

Pollutants Increase Song Complexity and the Volume of the Brain Area HVC in a Songbird

Environmental pollutants which alter endocrine function are now known to decrease vertebrate reproductive success. There is considerable evidence for endocrine disruption from aquatic ecosystems, but knowledge is lacking with regard to the interface between terrestrial and aquatic ecosystems. Here, we show for the first time that birds foraging on invertebrates contaminated with environmental pollutants, show marked changes in both brain and behaviour. We found that male European starlings (Sturnus vulgaris) exposed to environmentally relevant levels of synthetic and natural estrogen mimics developed longer and more complex songs compared to control males, a sexually selected trait important in attracting females for reproduction. Moreover, females preferred the song of males which had higher pollutant exposure, despite the fact that experimentally dosed males showed reduced immune function. We also show that the key brain area controlling male song complexity (HVC) is significantly enlarged in the contaminated birds. This is the first evidence that environmental pollutants not only affect, but paradoxically enhance a signal of male quality such as song. Our data suggest that female starlings would bias their choice towards exposed males, with possible consequences at the population level. As the starling is a migratory species, our results suggest that transglobal effects of pollutants on terrestrial vertebrate physiology and reproduction could occur in birds

Structure-guided design of a domain-selective bromodomain and extra terminal N-terminal bromodomain chemical probe

Small molecule mediated disruption of the protein-protein interactions between acetylated histone tails and the tandem bromodomains of the bromodomain and extra terminal (BET) family of proteins is an important mechanism of action for the potential modulation of immuno-inflammatory and oncology disease. High quality chemical probes have proven invaluable in elucidating profound BET bromodomain biology, with seminal publications of both pan- and domain-selective BET family bromodomain inhibitors enabling academic and industrial research. To enrich the toolbox of structurally differentiated N-terminal bromodomain (BD1) BET family chemical probes, this work describes an analysis of the GSK BRD4 bromodomain dataset through a lipophilic efficiency lens, which enabled identification of a BD1 domain biased benzimidazole series. Structure guided growth targeting a key Asp/His BD1/BD2 switch enabled delivery of GSK023, a high-quality chemical probe with 300–1000-fold BET BD1 domain selectivity and a phenotypic cellular fingerprint consistent with BET bromodomain inhibition

Mating dances and the evolution of language: What’s the next step?

The Darwinian protolanguage hypothesis is one of the most popular theories of the evolution of human language. According to this hypothesis, language evolved through a three stage process involving general increases in intelligence, the emergence of grammatical structure as a result of sexual selection on protomusical songs, and finally the attachment of meaning to the components of those songs. The strongest evidence for the second stage of this process has been considered to be birdsong, and as a result researchers have investigated the existence of various forms of grammar in the production and comprehension of songs by birds. Here, we argue that mating dances are another relevant source of sexually-selected complexity that has until now been largely overlooked by proponents of Darwinian protolanguage, focusing especially on the dances of long-tailed manakins. We end by sketching several lines of research that should be pursued to determine the relevance of mating dances to the evolution of language