We present a comprehensive analysis of all ring systems (both heterocyclic and nonheterocyclic) in clinical trial compounds and FDA-approved drugs. We show 67% of small molecules in clinical trials comprise only ring systems found in marketed drugs, which mirrors previously published findings for newly approved drugs. We also show there are approximately 450 000 unique ring systems derived from 2.24 billion molecules currently available in synthesized chemical space, and molecules in clinical trials utilize only 0.1% of this available pool. Moreover, there are fewer ring systems in drugs compared with those in clinical trials, but this is balanced by the drug ring systems being reused more often. Furthermore, systematic changes of up to two atoms on existing drug and clinical trial ring systems give a set of 3902 future clinical trial ring systems, which are predicted to cover approximately 50% of the novel ring systems entering clinical trials.

The cell envelope of Gram-negative bacteria is composed of two membranes separated by a soluble region. Here, we report microsecond time scale coarse-grained molecular dynamics simulations of models of the Escherichia coli cell envelope that incorporate both membranes and various native membrane proteins. Our results predict that both the inner and outer membranes curve in a manner dependent on the size of the embedded proteins. The tightly cross-linked lipopolysaccharide molecules (LPS) of the outer membrane cause a strong coupling between the movement of proteins and lipids. While the flow of phospholipids is more random, their diffusion is nevertheless influenced by nearby proteins. Our results reveal protein-induced lipid sorting, whereby cardiolipin is significantly enriched within the vicinity of the water channel AqpZ and the multidrug efflux pump AcrBZ. In summary, our results provide unprecedented details of the intricate relationship between both membranes of E. coli and the proteins embedded within them.

Lipopolysaccharide (LPS) is an important component of the outer membrane of Gram-negative bacteria, contributing to the structural integrity of the bacterial cell wall and conferring resistance to chemical attack. The rough variant of LPS contains a conserved lipid A domain and complete core saccharide section, while the smooth variant additionally contains a terminal O-antigen chain. In the following, smooth LPS lipids are simulated in multicomponent membrane models using coarse-grained molecular dynamics. The simulations reveal that the lipid environment of smooth LPS lipids affects the orientation and clustering of their O-antigen chains. When the outer membrane leaflets contain smooth LPS lipids alone the O-antigen chains are packed tightly, leading to strong cohesive intermolecular interactions. When the outer leaflets incorporate interstitial phospholipids and rough LPS variants, the O-antigen chains are tilted and less tightly bound. The different packing of terminal O-antigen chains affects lipid mobility and the mechanical strength of the Gram-negative membrane models. Gram-negative membranes with outer leaflets of smooth LPS alone can withstand surface tensions (150 mNm-1) that cause the membrane models with rough LPS lipids and comparable phospholipid bilayers to rupture much more readily.

We use coarse-grain molecular simulations to investigate the structural and dynamics differences between an asymmetric and a symmetrical membrane, both containing beta barrel transmembrane proteins. We find in where the dynamics of the two leaflets differ greatly, the slowest leaflet dominates the structural effects and importance of protein-lipid interactions.

The outer membrane of Gram-negative bacteria has a highly complex asymmetrical architecture, containing a mixture of phospholipids in the inner leaflet and almost exclusively lipopolysaccharide (LPS) molecules in the outer leaflet. In E. coli, the outer membrane contains a wide range of proteins with a β barrel architecture, that vary in size from the smallest having eight strands to larger barrels composed of 22 strands. Here we report coarse-grained molecular dynamics simulations of six proteins from the E. coli outer membrane OmpA, OmpX, BtuB, FhuA, OmpF, and EstA in a range of membrane environments, which are representative of the in vivo conditions for different strains of E. coli. We show that each protein has a unique pattern of interaction with the surrounding membrane, which is influenced by the composition of the protein, the level of LPS in the outer leaflet, and the differing mobilities of the lipids in the two leaflets of the membrane. Overall we present analyses from over 200 μs of simulation for each protein.

In this laboratory experiment, sophomore-level organic chemistry students use a simple procedure to prepare a room-temperature liquid crystal, MBBA. The preparation can be carried out in about one hour with high yields. The students then prepare ordered samples of the liquid crystal and observe their optical properties. This exercise utilizes a fairly traditional laboratory preparation of a compound but also serves as an introduction to liquid crystals and materials chemistry. It has been quite popular with the students and has minimal equipment needs.

In this work we are presenting the coupling of the Dry Martini CG model for lipids with the lattice Boltzmann molecular dynamics technique that allows to include hydrodynamic interactions in implicit solvent CG simulations. We present the coupling of this force field with the OPEP CG model for proteins. These advances allow us to investigate systems and biophysical processes where the fluid environment and motion is key: for instance from vesicular and membrane fusion, shear effects, fluid transport across the membrane to protein aggregation in a membrane environment. We will showcase not only the basic coupling but also simulations of challenging systems, like a nanoreactor where enzymes, substrates and crowding proteins are confined by a lipid vesicle.

The outer membrane of Gram-negative bacteria is almost exclusively composed of lipopolysaccharide in its outer leaflet, whereas the inner leaflet contains a mixture of phospholipids. Lipopolysaccharide diffuses at least an order of magnitude slower than phospholipids, which can cause issues for molecular dynamics simulations in terms of adequate sampling. Here we test a number of simulation protocols for their ability to achieve convergence with reasonable computational effort using the MARTINI coarse-grained force-field. This is tested in the context both of potential of mean force (PMF) calculations for lipid extraction from membranes, and of lateral mixing within the membrane phase. We find that decoupling the cations that crosslink the lipopolysaccharide headgroups from the extracted lipid during PMF calculations is the best approach to achieve convergence comparable to that for phospholipid extraction. We also show that lateral lipopolysaccharide mixing/sorting is very slow and not readily addressable even with Hamiltonian replica exchange. We discuss why more sorting may be unrealistic for the short (microseconds) timescales we simulate and provide an outlook for future studies of lipopolysaccharide-containing membranes.