The plant Perilla frutescens is widely employed in Asian medicine. The active components of Perilla include cyclic terpenes, which have a diverse range of antimicrobial, anticancer, sedative, and anti-inflammatory properties, hinting at a membrane-mediated mechanism of action. We have used molecular dynamics (MD) simulations and isothermal titration calorimetry (ITC) to investigate the interaction of four terpenes with model lipid bilayers. The ITC and MD data are mostly in accordance. The terpenes partition into membranes, pack along the lipid tails, and alter bilayer structure and dynamics. Three of the four molecules could cross the bilayer. The carboxylate-group-containing terpene modifies headgroup repulsion and increases the area per lipid by more than 10%, in a manner reminiscent of membrane-thinning peptides and solvents such as DMSO. Our results support the possibility that at least some medicinal properties of volatile Perilla extracts might arise from interactions with the lipid bilayer component of biological membranes.

Lipid II is critical for peptidoglycan synthesis, which is the main component of the bacterial cell wall. Lipid II is a relatively conserved and important part of the cell wall biosynthesis pathway and is targeted by antibiotics such as the lantibiotics, which achieve their function by disrupting the biosynthesis of the cell wall. Given the urgent need for development of novel antibiotics to counter the growing threat of bacterial infection resistance, it is imperative that a thorough molecular-level characterization of the molecules targeted by antibiotics be achieved. To this end, we present a molecular dynamics simulation study of the conformational dynamics of Lipid II within a detailed model of the Staphylococcus aureus cell membrane. We show that Lipid II is able to adopt a range of conformations, even within the packed lipidic environment of the membrane. Our simulations also reveal dimerization of Lipid II mediated by cations. In the presence of the defensin peptide plectasin, the conformational lability of Lipid II allows it to form loose complexes with the protein, via a number of different binding modes.

We have designed and synthesised a double-headed nucleotide that presents two nucleobases in the interior of a dsDNA duplex. This nucleotide recognises and forms Watson-Crick base pairs with two complementary adenosines in a Watson-Crick framework. Furthermore, with judicious positioning in complementary strands, the nucleotide recognises itself through the formation of a T:T base pair. Thus, two novel nucleic acid motifs can be defined by using our double-headed nucleotide. Both motifs were characterised by UV melting experiments, CD and NMR spectroscopy and molecular dynamics simulations. Both motifs leave the thermostability of the native dsDNA duplex largely unaltered. Molecular dynamics calculations showed that the double-headed nucleotides are accommodated in the dsDNA by entirely local perturbations and that the modified duplexes retain an overall B-type geometry with the dsDNA unwound by around 25 or 60°, respectively, in each of the modified motifs. Both motifs can be accommodated twice in a dsDNA duplex without incurring any loss of stability and extrapolating from this observation and the results of modelling, it is conceivable that both can be multiplied several times within a dsDNA duplex. These new motifs extend the DNA recognition repertoire and may form the basis for a complete series of double-headed nucleotides based on all 16 base combinations of the four natural nucleobases. In addition, both motifs can be used in the design of nanoscale DNA structures in which a specific duplex twist is required.

Cholesterol (Chol) and ergosterol (Erg) are abundant and important sterols in the plasma membrane of mammalian and yeast cells, respectively. The effects of Chol and Erg on membrane properties, as well as their intracellular transport, can be studied with use of fluorescence probes mimicking both sterols as closely as possible. In the search for new and efficient Chol and Erg probes, we use a combination of theoretical methods to explore a series of analogs. The optical properties of the analogs (i.e. excitation energies, emission energies and oscillator strengths) are examined using time-dependent density functional theory (TDDFT) and their ability to mimic the effects of Chol and Erg on membranes is investigated with molecular dynamics (MD) simulations of each analog in a 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC) bilayer. From the set of analogs we find two probes (3a and 3b) to display favorable electronic transition properties as well as strong condensing abilities. These findings can lead to the use of new efficient probes and aid in the understanding of the structural features of Chol and Erg that impart to them their unique effects on lipid membranes.

We investigate the effects of two structurally similar small cyclic molecules: salicylic acid and perillic acid on a zwitterionic model lipid bilayer, and show that both molecules might have biological activity related to membrane thinning. Salicylic acid is a nonsteroidal antiinflammatory drug, some of the pharmacological properties of which arise from its interaction with the lipid bilayer component of the plasma membrane. Prior simulations show that salicylate orders zwitterionic lipid membranes. However, this is in conflict with Raman scattering and vesicle fluctuation analysis data, which suggest the opposite. We show using extensive molecular dynamics simulations, cumulatively >2.5 μs, that salicylic acid indeed disorders membranes with concomitant membrane thinning and that the conflict arose because prior simulations suffered from artifacts related to the sodium-ion induced condensation of zwitterionic lipids modeled by the Berger force field. Perillic acid is a terpenoid plant extract that has antiinfective and anticancer properties, and is extensively used in eastern medicine. We found that perillic acid causes large-scale membrane thinning and could therefore exert its antimicrobial properties via a membrane-lytic mechanism reminiscent of antimicrobial peptides. Being more amphipathic, perillic acid is more potent in disrupting lipid headgroup packing, and significantly modifies headgroup dipole orientation. Like salicylate, the membrane thinning effect of perillic acid is masked by the presence of sodium ions. As an alternative to sodium cations, we advocate the straightforward solution of using larger countercations like potassium or tetra-methyl-ammonium that will maintain electroneutrality but not interact strongly with, and thus not condense, the lipid bilayer.

A set of average atom-centered charges and polarizabilities has been developed for three types of phospholipids for use in polarizable embedding calculations. The lipids investigated are 1,2-dimyristoyl-sn-glycero-3-phosphocholine, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, and 1-palmitoyl-2-oleoyl-sn-glycerol-3-phospho-L-serine given their common use both in experimental and computational studies. The charges, and to a lesser extent the polarizabilities, are found to depend strongly on the molecular conformation of the lipids. Furthermore, the importance of explicit polarization is underlined for the description of larger assemblies of lipids, that is, membranes. In conclusion, we find that specially developed polarizable parameters are needed for embedding calculations in membranes, while common non-polarizable point-charge force fields usually perform well enough for structural and dynamical studies. © 2017 Wiley Periodicals, Inc.

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Properties of biomembranes are modified in presence of additives such as cholesterol (chol) or proteins. Azobenzene-cholesterol (azo-chol) is a photoactive variety of chol since its azo-headgroup exhibits a reversible change of the conformation upon illumination (365nm: trans to cis; 455nm: cis to trans). Quasielastic neutron scattering (QENS) was applied to resolve lipid dynamics within biomimetic membranes consisting of a 1-palmitoyl-2-oleoyl-sn-phosphatidyl-choline (POPC) matrix with embedded azo-chol in either of the two conformational states. A pure POPC membrane and also a POPC membrane with inactive chol were used as control systems. The results report on the fast intramolecular motion of the protons in the POPC chains, a slow hop diffusion and an even slower mode both of the whole POPC molecule. The intramolecular motion and the hop diffusion are modified by the presence of azochol in the host membrane as compared with the control systems, but do not depend on the isomerization state. The slowest mode is though sensitive to the isomerization. The findings show the capacity of azo-chol for tuning the dynamics and most probably also the structures of the host lipid membrane though photoactivation.