Supercomputer-Based Ensemble Docking Drug Discovery Pipeline with Application to Covid-19.

We present a supercomputer-driven pipeline for in silico drug discovery using enhanced sampling molecular dynamics (MD) and ensemble docking. Ensemble docking makes use of MD results by docking compound databases into representative protein binding-site conformations, thus taking into account the dynamic properties of the binding sites. We also describe preliminary results obtained for 24 systems involving eight proteins of the proteome of SARS-CoV-2. The MD involves temperature replica exchange enhanced sampling, making use of massively parallel supercomputing to quickly sample the configurational space of protein drug targets. Using the Summit supercomputer at the Oak Ridge National Laboratory, more than 1 ms of enhanced sampling MD can be generated per day. We have ensemble docked repurposing databases to 10 configurations of each of the 24 SARS-CoV-2 systems using AutoDock Vina. Comparison to experiment demonstrates remarkably high hit rates for the top scoring tranches of compounds identified by our ensemble approach. We also demonstrate that, using Autodock-GPU on Summit, it is possible to perform exhaustive docking of one billion compounds in under 24 h. Finally, we discuss preliminary results and planned improvements to the pipeline, including the use of quantum mechanical (QM), machine learning, and artificial intelligence (AI) methods to cluster MD trajectories and rescore docking poses.

Supercomputer-Based Ensemble Docking Drug Discovery Pipeline with Application to Covid-19.

We present a supercomputer-driven pipeline for in-silico drug discovery using enhanced sampling molecular dynamics (MD) and ensemble docking. We also describe preliminary results obtained for 23 systems involving eight protein targets of the proteome of SARS CoV-2. THe MD performed is temperature replica-exchange enhanced sampling, making use of the massively parallel supercomputing on the SUMMIT supercomputer at Oak Ridge National Laboratory, with which more than 1ms of enhanced sampling MD can be generated per day. We have ensemble docked repurposing databases to ten configurations of each of the 23 SARS CoV-2 systems using AutoDock Vina. We also demonstrate that using Autodock-GPU on SUMMIT, it is possible to perform exhaustive docking of one billion compounds in under 24 hours. Finally, we discuss preliminary results and planned improvements to the pipeline, including the use of quantum mechanical (QM), machine learning, and AI methods to cluster MD trajectories and rescore docking poses.

Food choice motives including sustainability during purchasing are associated with a healthy dietary pattern in French adults.

BACKGROUND: Sustainability has become a greater concern among consumers that may influence their dietary intake. Only a few studies investigated the relationship between sustainable food choice motives and diet and they focused on specific food groups. OBJECTIVE: This cross-sectional study aimed to assess the associations between food choice motives during purchasing, with a focus on sustainability, and dietary patterns in a large sample of French adults. DESIGN: Food choice motives were collected in 31,842 adults from the NutriNet-Santé study, using a validated 63 items questionnaire gathered into 9 dimension scores: ethics and environment, traditional and local production, taste, price, environmental limitation (i.e. not buying a food for environmental concerns), health, convenience, innovation and absence of contaminants. Dietary intake was assessed using at least three web-based 24-h food records. Three dietary patterns were obtained through factor analysis using principal component analysis. The associations between food choice motive dimension scores and dietary patterns were assessed using linear regression models, stratifying by sex. RESULTS: Individuals were more likely to have a "healthy diet" when they were more concerned by not buying a food for environmental concerns (only for 3rd tertile versus 1st tertile ßwomen=0.18, 95% CI=0.15-0.20, ßmen=0.20 95% CI=(0.15-0.25)), ethics and environment (women only, ß=0.05, 95% CI=0.02-0.08), absence of contaminants (women only, ß=0.05, 95% CI=0.01-0.07), local production (women only, ß=0.08, 95% CI=0.04-0.11), health (women only) and innovation (men only), and when they were less concerned by price. Individuals were also less likely to have traditional or western diets when they gave importance to food choice motive dimensions related to sustainability. CONCLUSION: Individuals, especially women, having higher concerns about food sustainability dimensions such as ethics and environment and local production, appear to have a healthier diet. Further longitudinal studies are required to better understand how sustainable concerns may influence long-term nutritional quality of the diet.

Digital antimicrobial susceptibility testing using the MilliDrop technology.

We present the MilliDrop Analyzer (MDA), a droplet-based millifluidic system for digital antimicrobial susceptibility testing (D-AST), which enables us to determine minimum inhibitory concentrations (MICs) precisely and accurately. The MilliDrop technology was validated by using resazurin for fluorescence readout, for comparison with standard methodology, and for conducting reproducibility studies. In this first assessment, the susceptibility of a reference Gram-negative strain Escherichia coli ATCC 25922 to gentamicin, chloramphenicol, and nalidixic acid were tested by the MDA, VITEK®2, and broth microdilution as a reference standard. We measured the susceptibility of clinically relevant Gram-positive strains of Staphylococcus aureus to vancomycin, including vancomycin-intermediate S. aureus (VISA), heterogeneous vancomycin-intermediate S. aureus (hVISA), and vancomycin-susceptible S. aureus (VSSA) strains. The MDA provided results which were much more accurate than those of VITEK®2 and standard broth microdilution. The enhanced accuracy enabled us to reliably discriminate between VSSA and hVISA strains.

Energy versus information based estimations of dissipation using a pair of magnetic colloidal particles.

Using the framework of stochastic thermodynamics, we present an experimental study of a doublet of magnetic colloidal particles that is manipulated by a time-dependent magnetic field. Because of hydrodynamic interactions, each bead experiences a state-dependent friction, which we characterize using a hydrodynamic model. In this work, we compare two estimates of the dissipation in this system: the first one is energy based since it relies on the measured interaction potential, while the second one is information based since it uses only the information content of the trajectories. While the latter only offers a lower bound of the former, we find it to be simple to implement and of general applicability to more complex systems.

Monitoring single-cell bioenergetics via the coarsening of emulsion droplets.

Microorganisms are widely used to generate valuable products, and their efficiency is a major industrial focus. Bioreactors are typically composed of billions of cells, and available measurements only reflect the overall performance of the population. However, cells do not equally contribute, and process optimization would therefore benefit from monitoring this intrapopulation diversity. Such monitoring has so far remained difficult because of the inability to probe concentration changes at the single-cell level. Here, we unlock this limitation by taking advantage of the osmotically driven water flux between a droplet containing a living cell toward surrounding empty droplets, within a concentrated inverse emulsion. With proper formulation, excreted products are far more soluble within the continuous hydrophobic phase compared to initial nutrients (carbohydrates and salts). Fast diffusion of products induces an osmotic mismatch, which further relaxes due to slower diffusion of water through hydrophobic interfaces. By measuring droplet volume variations, we can deduce the metabolic activity down to isolated single cells. As a proof of concept, we present the first direct measurement of the maintenance energy of individual yeast cells. This method does not require any added probes and can in principle apply to any osmotically sensitive bioactivity, opening new routes for screening, and sorting large libraries of microorganisms and biomolecules.

Diffusion through colloidal shells under stress.

The permeability of solids has long been associated with a diffusive process involving activated mechanism as originally envisioned by Eyring. Tensile stress can affect the activation energy but definitive experiments of the diffusion rate of species through a stressed solid are lacking. Here we use core-shell (liquid core-solid shell) colloidal particles that are sensitive to osmotic pressure to follow the permeation of encapsulated probes at various stresses. We unambiguously show that the tensile stress applied on colloidal shells linearly reduces the local energy barrier for diffusion.

Thermal expansion within a chain of magnetic colloidal particles.

We study the thermal expansion of chains formed by self-assembly of magnetic colloidal particles in a magnetic field. Using video microscopy, complete positional data of all the particles of the chains is obtained. By changing the ionic strength of the solution and the applied magnetic field, the interaction potential can be tuned. We analyze the thermal expansion of the chain using a simple model of a one-dimensional anharmonic crystal of finite size.

Measuring colloidal forces with the magnetic chaining technique.

In 1994 Leal Calderon et al. (Phys. Rev. Lett. 72, 2959 (1994)) introduced the magnetic chaining technique to directly probe the force-distance profile between colloidal particles. In this paper, we revisit this approach in two ways. First, we describe a new experimental design which allows us to utilize sample volumes as low as a few microliters, involving femtomoles of surface active macromolecules. Secondly, we extensively describe the characterization and preparation of the magnetic colloids, and we give a quantitative evaluation of performance and resolution of the technique in terms of force and interparticle separation.

Chiral colloidal clusters.

Chirality is an important element of biology, chemistry and physics. Once symmetry is broken and a handedness is established, biochemical pathways are set. In DNA, the double helix arises from the existence of two competing length scales, one set by the distance between monomers in the sugar backbone, and the other set by the stacking of the base pairs. Here we use a colloidal system to explore a simple forcing route to chiral structures. To do so we have designed magnetic colloids that, depending on both their shape and induced magnetization, self-assemble with controlled helicity. We model the two length scales with asymmetric colloidal dumbbells linked by a magnetic belt at their waist. In the presence of a magnetic field the belts assemble into a chain and the steric constraints imposed by the asymmetric spheres force the chain to coil. We show that if the size ratio between the spheres is large enough, a single helicity is adopted, right or left. The realization of chiral colloidal clusters opens up a new link between colloidal science and chemistry. These colloidal clusters may also find use as mesopolymers, as optical and light-activated structures, and as models for enantiomeric separation.

Kinetic study of coupled field-induced aggregation and sedimentation processes arising in magnetic fluids.

In this work, the kinetics of coupled aggregation and sedimentation processes arising in magnetic fluids has been studied. Aggregation was induced applying a constant uniaxial magnetic field. The time evolution of the cluster-size distribution and the weight-average chain length was monitored using optical microscopy and digital image analysis. The experimental results are compared with the corresponding solutions of Smoluchowski's equation. For this purpose, a recently proposed aggregation kernel was employed. When sedimentation effects are taken into account, the fits improve especially at long aggregation times.

Measuring the kinetics of biomolecular recognition with magnetic colloids.

We introduce a general methodology based on magnetic colloids to study the recognition kinetics of tethered biomolecules. Access to the full kinetics of the reaction is provided by an explicit measure of the time evolution of the reactant densities. Binding between a single ligand and its complementary receptor is here limited by the colloidal rotational diffusion. It occurs within a binding distance that can be extracted by a reaction-diffusion theory that properly accounts for the rotational Brownian dynamics. Our reaction geometry allows us to probe a large diversity of bioadhesive molecules and tethers, thus providing a quantitative guidance for designing more efficient reactive biomimetic surfaces, as required for diagnostic, therapeutic, and tissue engineering techniques.

Prediction uncertainty of environmental change effects on temperate European biodiversity.

Observed patterns of species richness at landscape scale (gamma diversity) cannot always be attributed to a specific set of explanatory variables, but rather different alternative explanatory statistical models of similar quality may exist. Therefore predictions of the effects of environmental change (such as in climate or land cover) on biodiversity may differ considerably, depending on the chosen set of explanatory variables. Here we use multimodel prediction to evaluate effects of climate, land-use intensity and landscape structure on species richness in each of seven groups of organisms (plants, birds, spiders, wild bees, ground beetles, true bugs and hoverflies) in temperate Europe. We contrast this approach with traditional best-model predictions, which we show, using cross-validation, to have inferior prediction accuracy. Multimodel inference changed the importance of some environmental variables in comparison with the best model, and accordingly gave deviating predictions for environmental change effects. Overall, prediction uncertainty for the multimodel approach was only slightly higher than that of the best model, and absolute changes in predicted species richness were also comparable. Richness predictions varied generally more for the impact of climate change than for land-use change at the coarse scale of our study. Overall, our study indicates that the uncertainty introduced to environmental change predictions through uncertainty in model selection both qualitatively and quantitatively affects species richness projections.

Acceleration of the recognition rate between grafted ligands and receptors with magnetic forces.

When ligands and receptors are both attached on surfaces, because of the restriction of configurational freedom, their recognition kinetics may be substantially reduced as compared with freely diffusing species. In nature, this reduction may influence the efficiency of the capture and adhesion of circulating cells. Here we show that similar consequences are observed for colloids grafted with biomolecules that are used as probes for diagnostics. We exploit Brownian magnetic colloids that self-assemble into linear chains to show also that the resulting one-dimensional confinement considerably accelerates the recognition rate between grafted receptors and their ligands. We propose that because confinement significantly augments the colliding frequency, it also causes a large increase in the attempt frequency of the recognition. This work gives the basis of a rapid, homogeneous, and highly sensitive bioanalysis method.

Magnetic force probe for nanoscale biomolecules.

We present a new technique to measure the mechanical properties of small biomolecules. This technique uses long range repulsive colloidal forces together with magnetic attraction as a force probing tool. The biomolecules are grafted between superparamagnetic particles, which are regularly spaced within long chains maintained by an external magnetic field. Varying the magnetic field results in compression or extension of the molecules between the particles. In order to demonstrate this technique we use, as a size controlled model molecule, a short double stranded DNA (151 base pairs) for which the force-extension law is determined and found in agreement with existing predictions.

Growth below and above the spinodal limit: the cholesteric-nematic front.

In classical crystal growth, the solid propagates into its metastable liquid, even in the fast-dynamics regime in which kinetic effects dominate the diffusive effects. In usual experiments, the liquid is always very far from its spinodal limit below which it becomes unstable. For that reason, very little is known about crystal growth just below and above the spinodal limit of the liquid. In order to tackle this problem, we have performed an experiment about the propagation of the cholesteric-nematic front in directional melting. We show experimentally that, in this system, it is possible to reach and pass the spinodal limit. We show the existence of many morphological transitions at increasing velocities which lead to the formation of metastable or unstable phases. A complete phase diagram is drawn up as a function of the front velocity and the sample thickness. In particular, the crossing of the spinodal limit is clearly identified by comparison with the morphologies observed in free growth (i.e., at a homogeneous temperature). We show that this passage is accompanied by a reversal (pi rotation) of the structure in thin samples only. This spectacular effect resembles a "cell-to-dendrite" transition and is chirality induced. The importance of the first-order character of the transition is also emphasized.

Flexible magnetic filaments as micromechanical sensors.

We propose a new micromechanical approach to probe bending rigidity at molecular scale. Long flexible filaments made of magnetic colloids and linkers are shown to adopt under magnetic field a hairpin configuration. Measuring the hairpin curvature as a function of the field intensity and the linker length from diffracted light allows us to deduce the linker bending rigidity kappa. The technique is presented for two types of linkers: a spontaneously adsorbing polymer and a grafted biomolecular.

Nanorheology: An investigation of the boundary condition at hydrophobic and hydrophilic interfaces.

It has been shown that the flow of a simple liquid over a solid surface can violate the so-called no-slip boundary condition. We investigate the flow of polar liquids, water and glycerol, on a hydrophilic Pyrex surface and a hydrophobic surface made of a Self-Assembled Monolayer of OTS (octadecyltrichlorosilane) on Pyrex. We use a Dynamic Surface Force Apparatus (DSFA) which allows one to study the flow of a liquid film confined between two surfaces with a nanometer resolution. No-slip boundary conditions are found for both fluids on hydrophilic surfaces only. Significant slip is found on the hydrophobic surfaces, with a typical length of one hundred nanometers.