Conformational States of Melittin at a Bilayer Interface

AbstractThe distribution of peptide conformations in the membrane interface is central to partitioning energetics. Molecular-dynamics simulations enable characterization of in-membrane structural dynamics. Here, we describe melittin partitioning into dioleoylphosphatidylcholine lipids using CHARMM and OPLS force fields. Although the OPLS simulation failed to reproduce experimental results, the CHARMM simulation reported was consistent with experiments. The CHARMM simulation showed melittin to be represented by a narrow distribution of folding states in the membrane interface

A New Version of Reimers' law of Mass Loss Based on a Physical Approach

We present a new semi-empirical relation for the mass loss of cool stellar winds, which so far has frequently been described by "Reimers' law". Originally, this relation was based solely on dimensional scaling arguments without any physical interpretation. In our approach, the wind is assumed to result from the spill-over of the extended chromosphere, possibly associated with the action of waves, especially Alfven waves, which are used as guidance in the derivation of the new formula. We obtain a relation akin to the original Reimers law, but which includes two new factors. They reflect how the chromospheric height depends on gravity and how the mechanical energy flux depends, mainly, on effective temperature. The new relation is tested and sensitively calibrated by modelling the blue end of the Horizontal Branch of globular clusters. The most significant difference from mass loss rates predicted by the Reimers relation is an increase by up to a factor of 3 for luminous late-type (super-)giants, in good agreement with observations.Comment: 12 pages, 4 figures, accepted by ApJ Letter

Determining Peptide Partitioning Properties via Computer Simulation

The transfer of polypeptide segments into lipid bilayers to form transmembrane helices represents the crucial first step in cellular membrane protein folding and assembly. This process is driven by complex and poorly understood atomic interactions of peptides with the lipid bilayer environment. The lack of suitable experimental techniques that can resolve these processes both at atomic resolution and nanosecond timescales has spurred the development of computational techniques. In this review, we summarize the significant progress achieved in the last few years in elucidating the partitioning of peptides into lipid bilayer membranes using atomic detail molecular dynamics simulations. Indeed, partitioning simulations can now provide a wealth of structural and dynamic information. Furthermore, we show that peptide-induced bilayer distortions, insertion pathways, transfer free energies, and kinetic insertion barriers are now accurate enough to complement experiments. Further advances in simulation methods and force field parameter accuracy promise to turn molecular dynamics simulations into a powerful tool for investigating a wide range of membrane active peptide phenomena

Flaring Up All Over -- Radio Activity in Rapidly-Rotating Late-Type M and L Dwarfs

We present Very Large Array observations of twelve late M and L dwarfs in the Solar neighborhood. The observed sources were chosen to cover a wide range of physical characteristics - spectral type, rotation, age, binarity, and X-ray and H\alpha activity - to determine the role of these properties in the production of radio emission, and hence magnetic fields. Three of the twelve sources, TVLM513-46546, 2MASS J0036159+182110, and BRI0021-0214, were observed to flare and also exhibit persistent emission, indicating that magnetic activity is not quenched at the bottom of the main sequence. The radio emission extends to spectral type L3.5, and there is no apparent decrease in the ratio of flaring luminosities to bolometric luminosities between M8-L3.5. Moreover, contrary to the significant drop in persistent H\alpha activity beyond spectral type M7, the persistent radio activity appears to steadily increase between M3-L3.5. Similarly, the radio emission from BRI0021-0214 violates the phenomenological relations between the radio and X-ray luminosities of coronally active stars, hinting that radio and X-ray activity are also uncorrelated at the bottom of the main sequence. The radio active sources that have measured rotational velocities are rapid rotators, Vsin(i)>30 km/sec, while the upper limits on radio activity in slowly-rotating late M dwarfs (Vsin(i)<10 km/sec) are lower than these detections. These observations provide tantalizing evidence that rapidly-rotating late M and L dwarfs are more likely to be radio active. This possible correlation is puzzling given that the observed radio emission requires sustained magnetic fields of 10-1000 G and densities of 10^12 cm^-3, indicating that the active sources should have slowed down considerably due to magnetic braking.Comment: Accepted to ApJ; Two new figures; Minor text revision

Conformational Preferences of a 14-Residue Fibrillogenic Peptide from Acetylcholinesterase†

A 14-residue fragment from near the C-terminus of the enzyme acetylcholinesterase (AChE) is believed to have a neurotoxic/neurotrophic effect acting via an unknown pathway. While the peptide is α-helical in the full-length enzyme, the structure and association mechanism of the fragment are unknown. Using multiple molecular dynamics simulations, starting from a tetrameric complex of the association domain of AChE and systematicall disassembled subsets that include the peptide fragment, we show that the fragment is incapable of retaining its helicity in solution. Extensive replica exchange Monte Carlo folding and unfolding simulations in implicit solvent with capped and uncappted termini failed to converge to any consistent cluster of structures, suggesting that the fragment remains largely unstructured in solution under the conditions considered. Furthermore, extended molecular dynamics simulations of two steric zipper models show that the peptide is likely to form a zipper with antiparallel sheets and that peptides with mutations known to prevent fibril formation likely do so by interfering with this packing. The results demonstrate how the local environment of a peptide can stabilize a particular conformation

Tracking magnetic bright point motions through the solar atmosphere

High-cadence, multiwavelength observations and simulations are employed for the analysis of solar photospheric magnetic bright points (MBPs) in the quiet Sun. The observations were obtained with the Rapid Oscillations in the Solar Atmosphere (ROSA) imager and the Interferometric Bidimensional Spectrometer at the Dunn Solar Telescope. Our analysis reveals that photospheric MBPs have an average transverse velocity of approximately 1 km s−1, whereas their chromospheric counterparts have a slightly higher average velocity of 1.4 km s−1. Additionally, chromospheric MBPs were found to be around 63 per cent larger than the equivalent photospheric MBPs. These velocity values were compared with the output of numerical simulations generated using the MURAM code. The simulated results were similar, but slightly elevated, when compared to the observed data. An average velocity of 1.3 km s−1 was found in the simulated G-band images and an average of 1.8 km s−1 seen in the velocity domain at a height of 500 km above the continuum formation layer. Delays in the change of velocities were also analysed. Average delays of ∼4 s between layers of the simulated data set were established and values of ∼29 s observed between G-band and Ca II K ROSA observations. The delays in the simulations are likely to be the result of oblique granular shock waves, whereas those found in the observations are possibly the result of a semi-rigid flux tube

Free energy barrier for melittin reorientation from a membrane-bound state to a transmembrane state

An important step in a phospholipid membrane pore formation by melittin antimicrobial peptide is a reorientation of the peptide from a surface into a transmembrane conformation. In this work we perform umbrella sampling simulations to calculate the potential of mean force (PMF) for the reorientation of melittin from a surface-bound state to a transmembrane state and provide a molecular level insight into understanding peptide and lipid properties that influence the existence of the free energy barrier. The PMFs were calculated for a peptide to lipid (P/L) ratio of 1/128 and 4/128. We observe that the free energy barrier is reduced when the P/L ratio increased. In addition, we study the cooperative effect; specifically we investigate if the barrier is smaller for a second melittin reorientation, given that another neighboring melittin was already in the transmembrane state. We observe that indeed the barrier of the PMF curve is reduced in this case, thus confirming the presence of a cooperative effect

O VI Observations of the Onset of Convection Zones in Main-Sequence A Stars

If magnetic activity in outer stellar atmospheres is due to an interplay between rotation and subsurface convection, as is generally presumed, then one would not expect to observe indicators of activity in stars with T_eff > 8300 K. Any X-ray or ultraviolet line emission from hotter stars must be due either to a different mechanism or to an unresolved, active, binary companion. Due to their poor spatial resolution, X-ray instruments have been especially susceptible to source confusion. At wavelengths longward of 1216 Angstroms, the near ultraviolet spectra of stars hotter than this putative dividing line are dominated by photospheric continuum. We have used FUSE to obtain spectra of the subcoronal O VI emission lines, which lie at a wavelength where the photospheric continuum of the mid- and early-A stars is relatively weak. We observed 14 stars spanning a range in T_eff from 7720 to 10,000 K. Eleven of the 14 stars showed O VI emission lines, including 6 of the 8 targets with T_eff > 8300 K. At face value, this suggests that activity does not fall off with increasing temperature. However, the emission lines are narrower than expected from the projected rotational velocities of these rapidly-rotating stars, suggesting that the emission could come from unresolved late-type companions. Furthermore, the strength of the O VI emission is consistent with that expected from an unseen active K or M dwarf binary companinon, and the high x-ray to far uv luminosity ratios observed indicate that this must be the case. Our results are therefore consistent with earlier studies that have shown a rapid drop-off in activity at the radiative/convective boundary expected at T_eff about 8300 K, in agreement with conventional stellar structure models

Integrated Design of a Membrane-Lytic Peptide-Based Intravenous Nanotherapeutic Suppresses Triple-Negative Breast Cancer.

Funder: KCL PhD scholarshipsFunder: Leverhulme Trust; Id: http://dx.doi.org/10.13039/501100000275Membrane-lytic peptides offer broad synthetic flexibilities and design potential to the arsenal of anticancer therapeutics, which can be limited by cytotoxicity to noncancerous cells and induction of drug resistance via stress-induced mutagenesis. Despite continued research efforts on membrane-perforating peptides for antimicrobial applications, success in anticancer peptide therapeutics remains elusive given the muted distinction between cancerous and normal cell membranes and the challenge of peptide degradation and neutralization upon intravenous delivery. Using triple-negative breast cancer as a model, the authors report the development of a new class of anticancer peptides. Through function-conserving mutations, the authors achieved cancer cell selective membrane perforation, with leads exhibiting a 200-fold selectivity over non-cancerogenic cells and superior cytotoxicity over doxorubicin against breast cancer tumorspheres. Upon continuous exposure to the anticancer peptides at growth-arresting concentrations, cancer cells do not exhibit resistance phenotype, frequently observed under chemotherapeutic treatment. The authors further demonstrate efficient encapsulation of the anticancer peptides in 20 nm polymeric nanocarriers, which possess high tolerability and lead to effective tumor growth inhibition in a mouse model of MDA-MB-231 triple-negative breast cancer. This work demonstrates a multidisciplinary approach for enabling translationally relevant membrane-lytic peptides in oncology, opening up a vast chemical repertoire to the arms race against cancer

Detection of H Alpha Emission in a Methane (T-Type) Brown Dwarf

We report the detection of H{$\alpha$} emission in the T dwarf (methane brown dwarf) 2MASSW J1237392+652615 over three days using the Keck Low Resolution Imaging Spectrograph. The measured line flux, log(L$_{H{\alpha}}$/L$_{bol}$) = $-$4.3, is roughly consistent with early M dwarf activity levels and inconsistent with decreasing activity trends in late M and L dwarfs. Similar emission is not seen in two other T dwarfs. We speculate on several mechanisms that may be responsible for emission, including a strong magnetic field, continuous flaring, acoustic heat generation, and a close ($a$ $\sim$ 4 - 20 R$_{Jup}$) interacting binary, with the cooler component overflowing its Roche lobe. We suggest that the M9.5Ve PC 0025+0447 could be a warm analogue to 2MASS J1237+65, and may be powered by the latter mechanism.Comment: 14 pages, 3 figures, accepted by A