An Ensemble-Based Protocol for the Computational Prediction of Helix-Helix Interactions in G Protein-Coupled Receptors using Coarse-Grained Molecular Dynamics

The accurate identification of the specific points of interaction between G protein-coupled receptor (GPCR) oligomers is essential for the design of receptor ligands targeting oligomeric receptor targets. A coarse-grained molecular dynamics computer simulation approach would provide a compelling means of identifying these specific protein–protein interactions and could be applied both for known oligomers of interest and as a high-throughput screen to identify novel oligomeric targets. However, to be effective, this in silico modeling must provide accurate, precise, and reproducible information. This has been achieved recently in numerous biological systems using an ensemble-based all-atom molecular dynamics approach. In this study, we describe an equivalent methodology for ensemble-based coarse-grained simulations. We report the performance of this method when applied to four different GPCRs known to oligomerize using error analysis to determine the ensemble size and individual replica simulation time required. Our measurements of distance between residues shown to be involved in oligomerization of the fifth transmembrane domain from the adenosine A2A receptor are in very good agreement with the existing biophysical data and provide information about the nature of the contact interface that cannot be determined experimentally. Calculations of distance between rhodopsin, CXCR4, and β1AR transmembrane domains reported to form contact points in homodimers correlate well with the corresponding measurements obtained from experimental structural data, providing an ability to predict contact interfaces computationally. Interestingly, error analysis enables identification of noninteracting regions. Our results confirm that GPCR interactions can be reliably predicted using this novel methodology

We should just be told to try our best

Exam anxiety is a serious issue affecting a significant number of students across the globe. Recent changes to the GCSE curriculum and modes of assessment in England have coincided with concerning findings regarding associated increases in exam anxiety in secondary school students, which itself is linked to detrimental effects on mental health, learning and achievement. Dr Laura Nicholson and Prof Dave Putwain provide an overview of exam anxiety, its effects and what psychologists can do to help reduce it

Warning Students of the Consequences of Examination Failure: An Effective Strategy for Promoting Student Engagement?

In the context of high-stakes qualifications, teachers may warn students of the negative consequences of failure as a tactic designed to increase engagement and ultimately achievement. Previous studies have shown that these types of messages, namely fear appeals, are indirectly related to engagement and achievement in different ways depending on how they are evaluated by the student. When fear appeals are evaluated as a challenge, they are positively related to engagement and achievement. When evaluated as a threat, fear appeals are negatively related to engagement and achievement. In the present study, we offer a robust test of these relations in a multi-level model that controls for autoregressive and concurrent relations in the domain of mathematics. Self-reported data were collected from 1,530 participants, aged 14-16 years, at two time points over the final two years of secondary education. These data were linked to prior and subsequent achievement. Results showed that students who attended to fear appeals and evaluated them as a challenge showed higher subsequent engagement, and students who showed higher engagement showed higher achievement. Accordingly, it may be beneficial to identify those students likely to evaluate fear appeals as a threat and intervene in order to enhance the likelihood of a challenge evaluation (e.g., building confidence through strategy focused feedback and strengthening beliefs in the value of effort). Given the difficulties associated with teachers judging students’ motivation and emotion as private experiences, methods to access student voice should be considered

Achievement goals, behavioural engagement, and mathematics achievement: A mediational analysis

Previous studies have shown that mastery-approach and performance-approach goals can be positively associated with adaptive educational outcomes. Few studies, however, have examined links with behavioural engagement. The aim of the present study was to examine whether behavioural engagement mediated relations between mastery-approach and performance-approach goals and subsequent achievement in mathematics. Data were collected from 1057 students aged 9 to 11 years in a longitudinal design over the course of a single school year. Results showed that a mastery-approach, but not a performance-approach, goal predicted behavioural engagement. Behavioural engagement, in turn, predicted mathematics achievement. Furthermore, behavioural engagement mediated relations between mastery-approach and subsequent mathematics achievement. This study contributes to the evidence base for the adaptive role of mastery-approach which can be encouraged by students setting personal best goals, teachers ensuring that feedback is task-focused, and that the classroom climate is mastery-focused

Hit-to-lead and lead optimization binding free energy calculations for G protein-coupled receptors

We apply the hit-to-lead ESMACS (enhanced sampling of molecular dynamics with approximation of continuum solvent) and lead-optimization TIES (thermodynamic integration with enhanced sampling) methods to compute the binding free energies of a series of ligands at the A1 and A2A adenosine receptors, members of a subclass of the GPCR (G protein-coupled receptor) superfamily. Our predicted binding free energies, calculated using ESMACS, show a good correlation with previously reported experimental values of the ligands studied. Relative binding free energies, calculated using TIES, accurately predict experimentally determined values within a mean absolute error of approximately 1 kcal mol−1. Our methodology may be applied widely within the GPCR superfamily and to other small molecule–receptor protein systems

Bistability in Apoptosis by Receptor Clustering

Apoptosis is a highly regulated cell death mechanism involved in many physiological processes. A key component of extrinsically activated apoptosis is the death receptor Fas, which, on binding to its cognate ligand FasL, oligomerize to form the death-inducing signaling complex. Motivated by recent experimental data, we propose a mathematical model of death ligand-receptor dynamics where FasL acts as a clustering agent for Fas, which form locally stable signaling platforms through proximity-induced receptor interactions. Significantly, the model exhibits hysteresis, providing an upstream mechanism for bistability and robustness. At low receptor concentrations, the bistability is contingent on the trimerism of FasL. Moreover, irreversible bistability, representing a committed cell death decision, emerges at high concentrations, which may be achieved through receptor pre-association or localization onto membrane lipid rafts. Thus, our model provides a novel theory for these observed biological phenomena within the unified context of bistability. Importantly, as Fas interactions initiate the extrinsic apoptotic pathway, our model also suggests a mechanism by which cells may function as bistable life/death switches independently of any such dynamics in their downstream components. Our results highlight the role of death receptors in deciding cell fate and add to the signal processing capabilities attributed to receptor clustering.Comment: Accepted by PLoS Comput Bio

Expectancy of Success, Attainment Value, Engagement, and Achievement: A Moderated Mediation Analysis

The aim of this study was to examine how expectancy of success, attainment value, and their interaction predict behavioural engagement, and how behavioural engagement, in turn, predict achievement. Data were collected from 586 English students aged 10-11 years in their final year of primary school. Expectancy of success was positively related to subsequent achievement directly and indirectly, mediated by behavioural engagement over and above the variance accounted for by prior achievement and behavioural engagement. Indirect relations from expectancy of success to achievement were moderated by attainment value. Higher attainment value protected performance from low expectancy of success by increasing behavioural engagement. The compensatory role of high attainment value diminished at higher levels of expectancy of success

Expectancy of Success, Attainment Value, Engagement, and Achievement: A Moderated Mediation Analysis

The aim of this study was to examine how expectancy of success, attainment value, and their interaction predict behavioural engagement, and how behavioural engagement, in turn, predict achievement. Data were collected from 586 English students aged 10-11 years in their final year of primary school. Expectancy of success was positively related to subsequent achievement directly and indirectly, mediated by behavioural engagement over and above the variance accounted for by prior achievement and behavioural engagement. Indirect relations from expectancy of success to achievement were moderated by attainment value. Higher attainment value protected performance from low expectancy of success by increasing behavioural engagement. The compensatory role of high attainment value diminished at higher levels of expectancy of success