Heat and charge transport in H2O at ice-giant conditions from ab initio molecular dynamics simulations

The impact of the inner structure and thermal history of planets on their observable features, such as luminosity or magnetic field, crucially depends on the poorly known heat and charge transport properties of their internal layers. The thermal and electric conductivities of different phases of water (liquid, solid, and super-ionic) occurring in the interior of ice giant planets, such as Uranus or Neptune, are evaluated from equilibrium ab initio molecular dynamics, leveraging recent progresses in the theory and data analysis of transport in extended systems. The implications of our findings on the evolution models of the ice giants are briefly discussed

On the Binding Free Energy and Molecular Origin of Sickle Cell Hemoglobin Aggregation

International audienceProtein aggregation is associated with various diseases, including Alzheimer and Parkinson as well as sickle cell disease (SCD). From a molecular point of view, protein aggregation depends on a complex balance of electrostatic and hydrophobic interactions mediated by water. An impressive manifestation of the importance of this balance concerns the human hemoglobin (HbA) mutant, HbS (sickle cell Hb), where a single substitution at the 6th position of HbA β-chains, from glutamic acid to valine, causes the polymerization of deoxygenated HbS (deoxy-HbS), responsible for SCD. HbS polymerization is believed to occur via a double nucleation mechanism initiated by the formation of HbS fibers (homogeneous nucleation), followed by fiber growth. Furthermore, it was proposed that homogeneous nucleation proceeds through a two-step mechanism, where metastable dense clusters play the role of nucleation precursors. Thus, hindering or delaying the formation of such precursors could represent a potential SCD therapeutic route. Here, we study, through molecular dynamics, the binding free energy and protein–protein contacts involved in the deoxy-HbS dimer aggregation and stabilization process. A binding free energy of ∼−14.0 ± 1 kcal/mol is estimated from a one-dimensional potential of mean force. Analysis of protein–protein interactions shows that both electrostatic and van der Waals interactions play an important role on the aggregation of HbS. With respect to the former, our results indicate that aggregation is largely favored by the formation of salt bridges (SB), mostly, Lys–Glu, Lys–Asp, and Heme-Lys SB, which outweigh electrostatic repulsions involving similar residues. Thus, our results suggest that a potential antisickling drug could be one with the ability to weaken or hinder the formation of a few SB between carboxylate and ammonium groups

Mechanistic Insights into Polyphenols’ Aggregation Inhibition of α‑Synuclein and Related Peptides

While several polyphenols were found to either inhibit or modulate the aggregation of proteins implicated in neurodegenerative diseases, such as Parkinson’s disease (PD), discrepant action mechanisms have been reported. This, in addition to some polyphenols’ pan-assay interference compounds’ reputation, casts some doubts concerning their therapeutic relevance. Here, we studied, through molecular dynamics and enhanced sampling methods, the aggregation of 11-mer peptides from the non-amyloid-β component, an aggregation-prone domain of α-synuclein (α-syn) implicated in PD and other synucleinopathies, in neat water and aqueous solutions of resveratrol (RSV) and gallic acid (GA). Further, simulations of the complete protein were carried out in aqueous urea, RSV, and GA solutions. Our results show that peptide aggregation is not disrupted by either phenolic compound. Thus, instead, intrusion of RSV and GA in the inter-peptide region induces a peptide–peptide re-orientation, favoring terminal interactions that manifest in the formation of barrierless solvent-separated configurations. Moreover, although the (poly)phenols induce a pronounced peptide dewetting at high concentrations, β-sheet-rich regions, a hallmark of α-syn aggregation, are not disrupted. Thus, our results indicate that, if anything, RSV and GA delay or modulate peptide aggregation at high concentrations via the stabilization of solvent-separated conformations as opposed to aggregation inhibition. Structural analysis of the full protein, however, shows that the (poly)phenols induce more extended conformations of α-syn, similar to urea, possibly also influencing its aggregation propensity. However, opposite to urea, the (poly)phenols reduce α-syn’s conformational space, likely due to steric effects and a slowdown of the solvent dynamics. These effects are concentration-dependent and possibly unattainable at therapeutic-relevant concentrations. These results suggest that the aggregation inhibition activity of RSV and GA in vitro should involve, instead, either the non-covalent binding to oligomeric intermediates or the stabilization of the monomer and/or oligomers through the formation of covalent bonds of the respective quinones with α-syn. In addition, the enhanced aggregation tendency of the peptides observed here could be associated with the formation of non-toxic oligomers, reported for some polyphenols

Conflicting Interpretations of Scientific Pedagogy

Not surprisingly historical studies have suggested that there is a distance between concepts of teaching methods, their interpretations and their actual use in the classroom. This issue, however, is not always pitched to the personal level in historical studies, which may provide an alternative insight on how teachers conceptualise and engage with concepts of teaching methods. This article provides a case study on this level of conceptualisation by telling the story of Rómulo de Carvalho, an educator from mid-twentieth century Portugal, who for over 40 years engaged with the heuristic and Socratic methods. The overall argument is that concepts of teaching methods are open to different interpretations and are conceptualised within the melting pot of external social pressures and personal teaching preferences. The practice and thoughts of Carvalho about teaching methods are scrutinised to unveil his conflicting stances: Carvalho was a man able to question the tenets of heurism, but who publicly praised the heurism-like “discovery learning” method years later. The first part of the article contextualises the arrival of heurism in Portugal and how Carvalho attacked its philosophical tenets. In the second part, it dwells on his conflicting positions in relation to pupil-centred approaches. The article concludes with an appreciation of the embedded conflicting nature of the appropriation of concepts of teaching methods, and of Carvalho’s contribution to the development of the philosophy of practical work in school science