Data-driven discovery of cardiolipin-selective small molecules by computational active learning

Subtle variations in the lipid composition of mitochondrial membranes can have a profound impact on mitochondrial function. The inner mitochondrial membrane contains the phospholipid cardiolipin, which has been demonstrated to act as a biomarker for a number of diverse pathologies. Small molecule dyes capable of selectively partitioning into cardiolipin membranes enable visualization and quantification of the cardiolipin content. Here we present a data-driven approach that combines a deep learning-enabled active learning workflow with coarse-grained molecular dynamics simulations and alchemical free energy calculations to discover small organic compounds able to selectively permeate cardiolipin-containing membranes. By employing transferable coarse-grained models we efficiently navigate the all-atom design space corresponding to small organic molecules with molecular weight less than ≈500 Da. After direct simulation of only 0.42% of our coarse-grained search space we identify molecules with considerably increased levels of cardiolipin selectivity compared to a widely used cardiolipin probe 10-N-nonyl acridine orange. Our accumulated simulation data enables us to derive interpretable design rules linking coarse-grained structure to cardiolipin selectivity. The findings are corroborated by fluorescence anisotropy measurements of two compounds conforming to our defined design rules. Our findings highlight the potential of coarse-grained representations and multiscale modelling for materials discovery and design.

We present a data-driven approach combining deep learning-enabled active learning with coarse-grained simulations and alchemical free energy calculations to discover small molecules to selectively permeate cardiolipin membranes.     

Structural analysis of pyrrolidinones

In the course of a study on pyrrolidinones, the crystal structures of four compounds, namely, methyl N‐[(4‐meth­oxy­phenyl)(3,4,5‐tri­meth­oxy­phenyl)­methyl]­pyro­glut­amate, C₂₃­H₂₇­NO₇, methyl N‐[naphthyl‐(3,4,5‐tri­meth­oxy­phenyl)­methyl]­pyro­glut­amate diacetyl peroxide, C₂₆­H₂₇­NO₆·‐0.5C₄H₆O₄, 5‐(3,4,5‐tri­meth­oxy­phenyl)‐1,2,3,11b‐tetrahy­dro‐5H‐naphtho­[1,8‐f,g]indol­izin‐3‐one, C₂₄­H₂₃­NO₄, and 5‐(3,4,5‐tri­meth­oxy­phenyl)‐1,2,3,5,12,12a‐hexa­hydro­naph­tho­[1,2‐f]indol­izine‐3,12‐dione, C₂₅­H₂₃­NO₅, are presented, compared and discussed.     

Cobalt‐Mediated Radical Polymerization of Vinyl Acetate in Miniemulsion: Very Fast Formation of Stable Poly(vinyl acetate) Latexes at Low Temperature

Summary: Poly(vinyl acetate) macroinitiators end‐capped by a Co(acac)₂ complex (PVAc–Co(acac)₂), prepared in bulk by cobalt‐mediated radical polymerization (CMRP), are used for the controlled radical polymerization of vinyl acetate in miniemulsion to give high‐molecular‐weight polymers and high monomer conversion. Stable poly(vinyl acetate) latexes with solid contents ranging from 25 to 30 wt.‐% are prepared within unusually short reaction times (∼1 h) at low temperatures (0–30 °C).

SEC chromatograms for the PVAc–Co(acac)₂ macroinitiator and PVAc latex obtained under ultrasonication for 6 min at 0 °C (79% monomer conversion).     

Mathematical Justification of the Obstacle Problem in the Case of a Shallow Shell

This paper deals with the asymptotic formulation and justification of a mechanical model for a shallow shell in frictionless unilateral contact with an obstacle. The first three parts of the paper concern the formulation of the equilibrium problem. Special attention is paid to the contact conditions, which are usual within two or three dimensional elasticity, but which are not so usual in shell theories. Lastly the limit problem is formulated in the main part of the paper and a convergence result is presented. Two points are worth stressing here. First, we point out that unlike classical bilateral shell models justifications, the functional framework of the present analysis involves cones. Secondly, while the cones result from a positivity condition on the boundary as long as the thickness parameter is finite, leading to a Signorini problem in the Sobolev space H ¹, the cone results from a positivity condition in the domain, giving rise to a so-called obstacle problem in the Sobolev space H ² at the limit.      

Determination of Background Concentrations of Ag,Pd, Pt and Au in Highly Mineralized Ground Waters at Sub-ng L–1 Concentrations by Online Matrix Separation/Pre-Concentration Coupled to ICP-SFMS

Though not regulated in directives such as the Water Framework Directive of the European Union, the investigation of geogenic background concentrations of certain elements such as precious metals is of increasing interest, in particular for the early detection of a potential environmental pollution due to the increased use in various industrial and technological applications and in medicine. However, the precise and accurate quantification of precious metals in natural waters is challenging due to the complex matrices and the ultra-low concentrations in the (sub-) ng L⁻¹ range. A methodological approach, based on matrix separation and pre-concentration on the strong anion exchange resin TEVA^® Resin in an online mode directly coupled to ICP-SFMS, has been developed for the determination of Ag, Pt, Pd and Au in ground water. Membrane desolvation sample introduction was used to reduce oxide-based spectral interferences, which complicate the quantification of these metals with high accuracy. To overcome errors arising from matrix effects—in particular, the highly varying major ion composition of the investigated ground water samples—an isotope dilution analysis and quantification based on standard additions, respectively, were performed. The method allowed to process four samples per hour in a fully automated mode. With a sample volume of only 8 mL, enrichment factors of 6–9 could be achieved, yielding detection limits <1 ng L⁻¹. Validation of the trueness was performed based on the reference samples. This method has been used for the analysis of the total concentrations of Ag, Pt, Pd and Au in highly mineralized ground waters collected from springs located in important geological fault zones of Austria’s territory. Concentrations ranges of 0.21–64.2 ng L⁻¹ for Ag, 0.65–6.26 ng L⁻¹ for Pd, 0.07–1.55 ng L⁻¹ for Pt and 0.26–1.95 ng L⁻¹ for Au were found.     

Recent developments in the design of functionalised polymeric microspheres

This paper is a brief survey on the preparation of latexes bearing covalently bonded functional groups using various routes. Recent methods are presented using water soluble functional (or surface active) initiators, monomers or macromonomers. For tailor synthesis, the copolymerisation approach of a basic monomer with a functional monomer under emulsifier-free conditions is generally the more suitable and versatile one. More progress should be pursued in this field in order to design better adapted chemical structures which will improve their use in radical-initiated heterogeneous conditions and favour surface incorporation.     

Differential Complexing by Cyclodextrin Twin-cavity Hosts

The twin-cavity cyclodextrin (1) in which the link is a dithiotrehalosyl unit, and the flexibly-linked dimer (2) were shown to distinguish between the heterocyclic guests 3 and 4 (clofazimine drug) in spite of the guests' small structural difference. Both cyclodextrin dimer hosts form 1:1 complexes with methyl orange and with 3, as shown by double reciprocal plots of UV-absorbance change and host concentration. However with 4, both host molecules formed a 2 : 1 (host : guest) complex . Since both dimer cavities are used to create this effect, it is a new type of selectivity for macrocyclic hosts.     

Electrodeposition of noble metal nanoparticles on carbon nanotubes

Noble metal nanoparticles can be electrodeposited on carbon nanotubes under potential control. The nanotube sidewalls serve both as the electrodeposition template and as the wire electrically connecting the deposited nanoparticles.     

Synthesis of amphiphilic polyelectrolyte block copolymers using “living” radical polymerization. Application as stabilizers in emulsion polymerization

This paper describes the synthesis of amphiphilic block copolymers composed of an ionic poly(styrenesulfonate) first segment and a hydrophobic polystyrene second one, using TEMPO-mediated “living” radical polymerization. These copolymers proved to be efficient stabilizers in the emulsion polymerization of styrene.