Peptide cargo tunes a network of correlated motions in human leukocyte antigens

Most biomolecular interactions are typically thought to increase the (local) rigidity of a complex, for example, in drug‐target binding. However, detailed analysis of specific biomolecular complexes can reveal a more subtle interplay between binding and rigidity. Here, we focussed on the human leucocyte antigen (HLA), which plays a crucial role in the adaptive immune system by presenting peptides for recognition by the αβ T‐cell receptor (TCR). The role that the peptide plays in tuning HLA flexibility during TCR recognition is potentially crucial in determining the functional outcome of an immune response, with obvious relevance to the growing list of immunotherapies that target the T‐cell compartment. We have applied high‐pressure/temperature perturbation experiments, combined with molecular dynamics simulations, to explore the drivers that affect molecular flexibility for a series of different peptide–HLA complexes. We find that different peptide sequences affect peptide–HLA flexibility in different ways, with the peptide cargo tuning a network of correlated motions throughout the pHLA complex, including in areas remote from the peptide‐binding interface, in a manner that could influence T‐cell antigen discrimination

Heat capacity changes for transition-state analogue binding and catalysis with human 5 '-methylthioadenosine phosphorylase

Human 5′-methylthioadenosine phosphorylase (MTAP) catalyzes the phosphorolysis of 5′-methylthioadenosine (MTA). Its action regulates cellular MTA and links polyamine synthesis to S-adenosylmethionine (AdoMet) salvage. Transition state analogues with picomolar dissociation constants bind to MTAP in an entropically driven process at physiological temperatures, suggesting increased hydrophobic character or dynamic structure for the complexes. Inhibitor binding exhibits a negative heat capacity change (−ΔCₚ), and thus the changes in enthalpy and entropy upon binding are strongly temperature-dependent. The ΔCₚ of inhibitor binding by isothermal titration calorimetry does not follow conventional trends and is contrary to that expected from the hydrophobic effect. Thus, ligands of increasing hydrophobicity bind with increasing values of ΔCₚ. Crystal structures of MTAP complexed to transition-state analogues MT-DADMe-ImmA, BT-DADMe-ImmA, PrT-ImmA, and a substrate analogue, MT-tubercidin, reveal similar active site contacts and overall protein structural parameters, despite large differences in ΔCₚ for binding. In addition, ΔCₚ values are not correlated with Kd values. Temperature dependence of presteady state kinetics revealed the chemical step for the MTAP reaction to have a negative heat capacity for transition state formation (−ΔCₚ‡). A comparison of the ΔCₚ‡ for MTAP presteady state chemistry and ΔCₚ for inhibitor binding revealed those transition-state analogues most structurally and thermodynamically similar to the transition state. Molecular dynamics simulations of MTAP apoenzyme and complexes with MT-DADMe-ImmA and MT-tubercidin show small, but increased dynamic motion in the inhibited complexes. Variable temperature CD spectroscopy studies for MTAP–inhibitor complexes indicate remarkable protein thermal stability (to Tₘ = 99 °C) in complexes with transition-state analogues

Interferometric imaging with the 32 element Murchison Wide-field Array

The Murchison Wide-field Array (MWA) is a low frequency radio telescope, currently under construction, intended to search for the spectral signature of the epoch of re-ionisation (EOR) and to probe the structure of the solar corona. Sited in Western Australia, the full MWA will comprise 8192 dipoles grouped into 512 tiles, and be capable of imaging the sky south of 40 degree declination, from 80 MHz to 300 MHz with an instantaneous field of view that is tens of degrees wide and a resolution of a few arcminutes. A 32-station prototype of the MWA has been recently commissioned and a set of observations taken that exercise the whole acquisition and processing pipeline. We present Stokes I, Q, and U images from two ~4 hour integrations of a field 20 degrees wide centered on Pictoris A. These images demonstrate the capacity and stability of a real-time calibration and imaging technique employing the weighted addition of warped snapshots to counter extreme wide field imaging distortions.Comment: Accepted for publication in PASP. This is the draft before journal typesetting corrections and proofs so does contain formatting and journal style errors, also has with lower quality figures for space requirement

A new layout optimization technique for interferometric arrays, applied to the MWA

Antenna layout is an important design consideration for radio interferometers because it determines the quality of the snapshot point spread function (PSF, or array beam). This is particularly true for experiments targeting the 21 cm Epoch of Reionization signal as the quality of the foreground subtraction depends directly on the spatial dynamic range and thus the smoothness of the baseline distribution. Nearly all sites have constraints on where antennas can be placed---even at the remote Australian location of the MWA (Murchison Widefield Array) there are rock outcrops, flood zones, heritages areas, emergency runways and trees. These exclusion areas can introduce spatial structure into the baseline distribution that enhance the PSF sidelobes and reduce the angular dynamic range. In this paper we present a new method of constrained antenna placement that reduces the spatial structure in the baseline distribution. This method not only outperforms random placement algorithms that avoid exclusion zones, but surprisingly outperforms random placement algorithms without constraints to provide what we believe are the smoothest constrained baseline distributions developed to date. We use our new algorithm to determine antenna placements for the originally planned MWA, and present the antenna locations, baseline distribution, and snapshot PSF for this array choice.Comment: 12 pages, 6 figures, 1 table. Accepted for publication in MNRA

The Murchison Widefield Array

It is shown that the excellent Murchison Radio-astronomy Observatory site allows the Murchison Widefield Array to employ a simple RFI blanking scheme and still calibrate visibilities and form images in the FM radio band. The techniques described are running autonomously in our calibration and imaging software, which is currently being used to process an FM-band survey of the entire southern sky.Comment: Accepted for publication in Proceedings of Science [PoS(RFI2010)016]. 6 pages and 3 figures. Presented at RFI2010, the Third Workshop on RFI Mitigation in Radio Astronomy, 29-31 March 2010, Groningen, The Netherland

The EoR Sensitivity of the Murchison Widefield Array

Using the final 128 antenna locations of the Murchison Widefield Array (MWA), we calculate its sensitivity to the Epoch of Reionization (EoR) power spectrum of red- shifted 21 cm emission for a fiducial model and provide the tools to calculate the sensitivity for any model. Our calculation takes into account synthesis rotation, chro- matic and asymmetrical baseline effects, and excludes modes that will be contaminated by foreground subtraction. For the fiducial model, the MWA will be capable of a 14{\sigma} detection of the EoR signal with one full season of observation on two fields (900 and 700 hours).Comment: 5 pages, 4 figures, 1 table, Accepted for publication in MNRAS Letters. Supplementary material will be available in the published version, or by contacting the author

The Murchison Widefield Array: the Square Kilometre Array Precursor at low radio frequencies

The Murchison Widefield Array (MWA) is one of three Square Kilometre Array Precursor telescopes and is located at the Murchison Radio-astronomy Observatory in the Murchison Shire of the mid-west of Western Australia, a location chosen for its extremely low levels of radio frequency interference. The MWA operates at low radio frequencies, 80-300 MHz, with a processed bandwidth of 30.72 MHz for both linear polarisations, and consists of 128 aperture arrays (known as tiles) distributed over a ~3 km diameter area. Novel hybrid hardware/software correlation and a real-time imaging and calibration systems comprise the MWA signal processing backend. In this paper the as-built MWA is described both at a system and sub-system level, the expected performance of the array is presented, and the science goals of the instrument are summarised.Comment: Submitted to PASA. 11 figures, 2 table

What traits are carried on mobile genetic elements, and why?

Although similar to any other organism, prokaryotes can transfer genes vertically from mother cell to daughter cell, they can also exchange certain genes horizontally. Genes can move within and between genomes at fast rates because of mobile genetic elements (MGEs). Although mobile elements are fundamentally self-interested entities, and thus replicate for their own gain, they frequently carry genes beneficial for their hosts and/or the neighbours of their hosts. Many genes that are carried by mobile elements code for traits that are expressed outside of the cell. Such traits are involved in bacterial sociality, such as the production of public goods, which benefit a cell's neighbours, or the production of bacteriocins, which harm a cell's neighbours. In this study we review the patterns that are emerging in the types of genes carried by mobile elements, and discuss the evolutionary and ecological conditions under which mobile elements evolve to carry their peculiar mix of parasitic, beneficial and cooperative genes