History-dependent Stress Relaxation of Liquids Under High-confinement: A Molecular Dynamics Study

When liquids are confined into nanometer-scale slit, the induced layering-like film structure allows the liquid to sustain non-isotropic stresses and thus being load-bearing. Such anisotropic characteristics of liquid under confinement arise naturally from the liquids’ wave number dependent compressibility that does not need solidification to take place as a prerequisite. In other words, liquids under confinement can still remain fluidity with molecules being (sub-)diffusive. However, the extensively prolonged structural relaxation time can cause hysteresis of stress relaxation of confined molecules in response to the motions of confining walls and thereby yield the quasi-static stress tensor history-dependent. In this work, by means of molecule dynamics, the discrepancy of stress tensor of a highly confined key base-oil component, i.e. 1-decene trimer, is captured after its relaxation from being compressed and decompressed. The results indicate that among the effects (e.g. confinement, molecular structure, and film density) that can potentially affect confined stress tensor, the ordering status of the confined molecules plays a predominant role.

Quantitative theory for the diffusive dynamics of liquid condensates

Key processes of biological condensates are diffusion and material exchange with their environment. Experimentally, diffusive dynamics are typically probed via fluorescent labels. However, to date, a physics-based, quantitative framework for the dynamics of labeled condensate components is lacking. Here we derive the corresponding dynamic equations, building on the physics of phase separation, and quantitatively validate the related framework via experiments. We show that by using our framework we can precisely determine diffusion coefficients inside liquid condensates via a spatio-temporal analysis of fluorescence recovery after photobleaching (FRAP) experiments. We showcase the accuracy and precision of our approach by considering space- and time-resolved data of protein condensates and two different polyelectrolyte-coacervate systems. Interestingly, our theory can also be used to determine a relationship between the diffusion coefficient in the dilute phase and the partition coefficient, without relying on fluorescence measurements in the dilute phase. This enables us to investigate the effect of salt addition on partitioning and bypasses recently described quenching artifacts in the dense phase. Our approach opens new avenues for theoretically describing molecule dynamics in condensates, measuring concentrations based on the dynamics of fluorescence intensities, and quantifying rates of biochemical reactions in liquid condensates.

Exploring dual agonists for PPARα/γ receptors using pharmacophore modeling, docking analysis and molecule dynamics simulation

Background: The peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear receptor family. The roles of PPARα in fatty acid oxidation and PPARγ in adipocyte differentiation and lipid storage have been widely characterized. Compounds with dual PPARα/γ activity have been proposed, combining the benefits of insulin sensitization and lipid-lowering into one drug, allowing a single drug to reduce hyperglycemia and hyperlipidemia while preventing the development of cardiovascular complications. Methods: The new PPARα/γ agonists were screened through virtual screening of pharmacophores and molecular dynamics simulations. First, in the article, the constructed pharmacophore was used to screen the Ligand Expo Components-pub database to obtain the common structural characteristics of representative PPARα/γ agonist ligands. Then, the obtained ligand structure was modified and replaced to obtain 12 new compounds. Using molecular docking, ADMET and molecular dynamics simulation methods, the designed 12 ligands were screened, their docking scores were analyzed when they bound to the PPARα/γ dual targets, and also their stability and pharmacological properties were assessed when they were bound to the PPARα/γ dual targets. Results: We performed pharmacophore-based virtual screening for 22949 molecules in the Ligand Expo Components-pub database. Structural analysis and modification were performed on the compounds that were superior to the original ligand , and a series of compounds with novel structures were designed. Using precise docking, ADMET prediction and molecular dynamics methods, newly designed compounds were screened and verified, and the above compounds showed higher docking scores and lower side effects. Conclusion: 9 new PPARα/γ agonists were obtained by pharmacophore modeling, docking analysis and molecule dynamics simulation.

Three-dimensional tracking of tethered particles for probing nanometer-scale single-molecule dynamics using plasmonic microscope

Three-dimensional (3D) tracking of surface-tethered single-particle reveals the dynamics of the molecular tether. However, most 3D tracking techniques lack precision, especially in axial direction, for measuring the dynamics of biomolecules with spatial scale of several nanometers. Here we present a plasmonic imaging technique that can track the motion of ~100 tethered particles in 3D simultaneously with sub-nanometer axial precision at millisecond time resolution. By tracking the 3D coordinates of tethered particle with high spatial resolution, we are able to determine the dynamics of single short DNA and study its interaction with enzyme. We further show that the particle motion pattern can be used to identify specific and non-specific interactions in immunoassays. We anticipate that our 3D tracking technique can contribute to the understanding of molecular dynamics and interactions at the single-molecule level.