On the Effect of Ions on Water Dynamics in Dilute and Concentrated Aqueous Salt Solutions

International audienceAqueous ionic solutions are ubiquitous in chemistry and in biology. Experiments show that ions affect water dynamics, but a full understanding of several questions remains needed: why some salts accelerate water dynamics while others slow it down, why the effect of a given salt can be concentration dependent, whether the effect of ions is rather local or more global. Numerical simulations are particularly suited to disentangle these different effects, but current force fields suffer from limitations and often lead to a poor description of dynamics in several aqueous salt solutions. Here, we develop an improved classical force field for the description of alkali halides which yields dynamics in excellent agreement with experimental measurements for water reorientational and translational dynamics. These simulations are analyzed with an extended jump model, which allows to compare the effects of ions on local hydrogen-bond exchange dynamics and on more global properties like viscosity. Our results unambiguously show that the ion-induced changes in water dynamics are usually mostly due to a local effect on the hydrogen-bond exchange dynamics; in contrast , the change in viscosity leads to a smaller effect, which governs the retardation only for a minority of salts and at high concentrations. We finally show how the respective importance of these two effects can be directly determined from experimental measurements alone, thus providing guidelines for the selection of an elec-trolyte with specific dynamical properties

Structural transitions in the RNA 7SK 5' hairpin and their effect on HEXIM binding.

7SK RNA, as part of the 7SK ribonucleoprotein complex, is crucial to the regulation of transcription by RNA-polymerase II, via its interaction with the positive transcription elongation factor P-TEFb. The interaction is induced by binding of the protein HEXIM to the 5' hairpin (HP1) of 7SK RNA. Four distinct structural models have been obtained experimentally for HP1. Here, we employ computational methods to investigate the relative stability of these structures, transitions between them, and the effects of mutations on the observed structural ensembles. We further analyse the results with respect to mutational binding assays, and hypothesize a mechanism for HEXIM binding. Our results indicate that the dominant structure in the wild type exhibits a triplet involving the unpaired nucleotide U40 and the base pair A43-U66 in the GAUC/GAUC repeat. This conformation leads to an open major groove with enough potential binding sites for peptide recognition. Sequence mutations of the RNA change the relative stability of the different structural ensembles. Binding affinity is consequently lost if these changes alter the dominant structure

Maternal outcomes and risk factors for COVID-19 severity among pregnant women.

Pregnant women may be at higher risk of severe complications associated with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which may lead to obstetrical complications. We performed a case control study comparing pregnant women with severe coronavirus disease 19 (cases) to pregnant women with a milder form (controls) enrolled in the COVI-Preg international registry cohort between March 24 and July 26, 2020. Risk factors for severity, obstetrical and immediate neonatal outcomes were assessed. A total of 926 pregnant women with a positive test for SARS-CoV-2 were included, among which 92 (9.9%) presented with severe COVID-19 disease. Risk factors for severe maternal outcomes were pulmonary comorbidities [aOR 4.3, 95% CI 1.9-9.5], hypertensive disorders [aOR 2.7, 95% CI 1.0-7.0] and diabetes [aOR2.2, 95% CI 1.1-4.5]. Pregnant women with severe maternal outcomes were at higher risk of caesarean section [70.7% (n = 53/75)], preterm delivery [62.7% (n = 32/51)] and newborns requiring admission to the neonatal intensive care unit [41.3% (n = 31/75)]. In this study, several risk factors for developing severe complications of SARS-CoV-2 infection among pregnant women were identified including pulmonary comorbidities, hypertensive disorders and diabetes. Obstetrical and neonatal outcomes appear to be influenced by the severity of maternal disease

Molecular interpretation of single-molecule force spectroscopy experiments with computational approaches

Single molecule force-spectroscopy techniques have granted access to unprecedented molecular-scale details about biochemical and biological mechanisms. However, the interpretation of the experimental data is often challenging and it benefits from the perspective brought by computational approaches. In many cases, these simulations (all-atom steered MD simulations in particular) are key to provide molecular details about the associated mechanisms, to help test different hypotheses and to predict experimental results. We will review here some of our recent efforts directed towards the molecular interpretation of single-molecule force spectroscopy experiments on proteins and protein-related systems, often in close collaboration with experimental groups. These results will be discussed in the broader contexts of the field, highlighting the recent achievements and the ongoing challenges for computational biophysicists and biochemists. In particular, we will focus on the input gained from molecular simulations approaches to rationalize the origins for the unfolded protein elasticity and the protein conformational behavior under force, to understand how force denaturation differs from chemical, thermal or shear unfolding, and to unravel the molecular details of unfolding events for a variety of systems. We will also discuss the use of models based on Langevin dynamics on a 1-D free-energy surface to understand the effect of protein segmentation on the work exerted by a force, or, at the other end of the spectrum of computational techniques, how quantum calculations can help to understand the reactivity of disulfide bridges exposed under force

Water and hydrogen-bond dynamics in aqueous systems (from bulk to biomolecular environments)

Des aspects clés de la dynamique de réorientation de l'eau ont été étudiés à l'aide de simulations numériques et de mod les analytiques, en forte connexion avec les résultats expérimentaux. Ce travail porte essentiellement sur le mécanisme moléculaire de la réorientation, qui implique des sauts angulaires de grande amplitude permettant l'échange de partenaires de liaisons hydrogènes. Ainsi, dans le cas du bulk, j'ai pu éclaircir quelques aspects fondamentaux de la dépendance en température de la réorientation, et ai proposé une interprétation de résultats expérimentaux récents de spectroscopie non linéaire. Par ailleurs, j'ai rationalisé l'effet de solutés très variés, comme des hydrophobes, des amphiphiles, et des surfaces étendues, sur la dynamique de l'eau. J'ai montré que la réorientation de l'eau n'est que faiblement ralentie par la présence de groupes hydrophobes, alors que les groupes hydrophiles peuvent avoir un effet bien plus important sur la dynamique. Ceci forme donc un cadre unique pour comprendre ultérieurement la dynamique de l'eau dans des systèmes plus complexes, en particulier les milieux biologiques.PARIS-BIUSJ-Biologie recherche (751052107) / SudocSudocFranceF

The force-dependent mechanism of DnaK-mediated mechanical folding

Mechanical force regulates the extent of chaperone binding to the protein substrate during mechanical folding.</jats:p

In silico all-atom approach to thermodiffusion in dilute aqueous solutions

Thermodiffusion (or thermophoresis) is the phenomenon by which the spatial distributions of constituents of liquid or gas phases become inhomogeneous in response to a temperature gradient. It has been evidenced in a variety of systems and has many practical applications, as well as implications in the context of the origins of life. A complete molecular picture of thermophoresis is still missing and phenomenological approaches are often employed to account for the experimental observations. In particular, the amplitude of the resulting concentration-gradients (quantified by the Soret coefficient) depends on many factors that are not straightforwardly rationalized. All-atom molecular dynamics simulations appear as an exquisite tool to shed light on the molecular origins for this phenomenon in molecular systems, but the practical implementation of thermophoretic settings in silico poses significant challenges. Here, we propose a robust approach to tackle thermophoresis in dilute realistic solutions at the molecular level. We rely on a recent enhanced heat-exchange algorithm to generate temperature-gradients. We carefully assess the convergence of thermophoretic simulations in dilute aqueous solutions. We show that simulations typically need to be propagated on long timescales (hundreds of nanoseconds). We find that the magnitude of the temperature gradient and the box sizes have little effect on the measured Soret coefficients. Practical guidelines are derived from such observations. Provided with this reliable setup, we discuss the results of thermophoretic simulations on several examples of molecular, neutral solutes, which we find in very good agreement with experimental measurements regarding the concentration-, mass-, and temperature-dependence of the Soret coefficient

Mass effects for thermodiffusion in dilute aqueous solutions

Thermodiffusion is the phenomenon by which molecules in a mixture present concentration gradients in response to an imposed temperature gradient. Despite decades of investigations, this effect remains poorly understood at a molecular level. A common, phenomenological approach is to individuate the molecular factors that influence the Soret coefficient, the parameter that quantifies the resulting concentration-gradient. Experimental studies, often performed on organic mixtures, as well as simulations of model particle systems have evidenced that the difference in masses between the mixture components has an important effect on the amplitude of the Soret coefficient. Here, we use molecular dynamics simulations of a thermophoretic setting to investigate the mass dependence of the Soret coefficient in dilute aqueous solutions. An advantage of simulation approaches is that they are not limited in the range of explored molecular masses, which is often limited to isotopic substitutions in the experiments. Our simulations reveal that the mass dependence of the Soret coefficient in these solutions is in agreement with previous experimental and simulation work on molecular-size systems. In particular, it is sensitive to the relative mass difference between the solute and the solvent, but not to their absolute mass. Adjusting the mass of the solvent and of the solute can turn a thermophobic solution into a thermophilic one, where solute accumulation is reversed. This demonstrates that the mass effect can indeed compensate for the other contributions to the Soret coefficient. Finally, we find that changing the molecular moments of inertia has a much more limited impact as compared to a change in the total molecular mass