Exploring ligand stability in protein crystal structures using binding pose metadynamics

Identification of correct protein-ligand binding poses is important in structure-based drug design and crucial for the evaluation of protein-ligand binding affinity. Protein-ligand coordinates are commonly obtained from crystallography experiments that provide a static model of an ensemble of conformations. Binding pose metadynamics (BPMD) is an enhanced sampling method that allows for an efficient assessment of ligand stability in solution. Ligand poses that are unstable under the bias of the metadynamics simulation are expected to be infrequently occupied in the energy landscape, thus making minimal contributions to the binding affinity. Here, the robustness of the method is studied using crystal structures with ligands known to be incorrectly modeled, as well as 63 structurally diverse crystal structures with ligand fit to electron density from the Twilight database. Results show that BPMD can successfully differentiate compounds whose binding pose is not supported by the electron density from those with well-defined electron density

Drought forecasting isn\u27t just about water- to get smart we need health and financial data too

The Millennium Drought taught Australians many lessons about living under extremely dry conditions – not just about how to conserve water, but also about human suffering. In a drought, farmers find it more difficult to make an income, leading to mental health problems and raising the rate of male suicides. In the city, the impact is felt through water restrictions and more expensive infrastructure. With very dry conditions returning to Tasmania, central Queensland and western Victoria, are we better prepared for the next big drought? This is an issue not just for Australia, but across the world, from California, to England, to the Levant region in the eastern Mediterranean, which from 1998-2012 experienced its worst drought in 900 years

Ensemble Simulations and Experimental Free Energy Distributions: Evaluation and Characterization of Isoxazole Amides as SMYD3 Inhibitors

Optimization of binding affinities for ligands to their target protein is a primary objective in rational drug discovery. Herein, we report on a collaborative study that evaluates various compounds designed to bind to the SET and MYND domain-containing protein 3 (SMYD3). SMYD3 is a histone methyltransferase and plays an important role in transcriptional regulation in cell proliferation, cell cycle, and human carcinogenesis. Experimental measurements using the scintillation proximity assay show that the distributions of binding free energies from a large number of independent measurements exhibit non-normal properties. We use ESMACS (enhanced sampling of molecular dynamics with approximation of continuum solvent) and TIES (thermodynamic integration with enhanced sampling) protocols to predict the binding free energies and to provide a detailed chemical insight into the nature of ligand-protein binding. Our results show that the 1-trajectory ESMACS protocol works well for the set of ligands studied here. Although one unexplained outlier exists, we obtain excellent statistical ranking across the set of compounds from the ESMACS protocol and good agreement between calculations and experiments for the relative binding free energies from the TIES protocol. ESMACS and TIES are again found to be powerful protocols for the accurate comparison of the binding free energies

Exploring the boundaries of microbial habitability in soil

© The Author(s), 2021. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Dragone, N. B., Diaz, M. A., Hogg, I., Lyons, W. B., Jackson, W. A., Wall, D. H., Adams, B. J., & Fierer, N. Exploring the boundaries of microbial habitability in soil. Journal of Geophysical Research: Biogeosciences, 126(6), (2021): e2020JG006052, https://doi.org/10.1029/2020JG006052.Microbes are widely assumed to be capable of colonizing even the most challenging terrestrial surface environments on Earth given enough time. We would not expect to find surface soils uninhabited by microbes as soils typically harbor diverse microbial communities and viable microbes have been detected in soils exposed to even the most inhospitable conditions. However, if uninhabited soils do exist, we might expect to find them in Antarctica. We analyzed 204 ice-free soils collected from across a remote valley in the Transantarctic Mountains (84–85°S, 174–177°W) and were able to identify a potential limit of microbial habitability. While most of the soils we tested contained diverse microbial communities, with fungi being particularly ubiquitous, microbes could not be detected in many of the driest, higher elevation soils—results that were confirmed using cultivation-dependent, cultivation-independent, and metabolic assays. While we cannot confirm that this subset of soils is completely sterile and devoid of microbial life, our results suggest that microbial life is severely restricted in the coldest, driest, and saltiest Antarctic soils. Constant exposure to these conditions for thousands of years has limited microbial communities so that their presence and activity is below detectable limits using a variety of standard methods. Such soils are unlikely to be unique to the studied region with this work supporting previous hypotheses that microbial habitability is constrained by near-continuous exposure to cold, dry, and salty conditions, establishing the environmental conditions that limit microbial life in terrestrial surface soils.This work was supported by grants from the U.S. National Science Foundation (ANT 1341629 to B. J. Adams, N. Fierer, W. Berry Lyons, and D. H. Wall and OPP 1637708 to B. J. Adams) with additional support provided to N. B. Dragone from University Colorado Department of Ecology and Evolutionary Biology

Elevational constraints on the composition and genomic attributes of microbial communities in Antarctic soils

© The Author(s), 2022. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Dragone, N. B., Henley, J. B., Holland-Moritz, H., Diaz, M., Hogg, I. D., Lyons, W. B., Wall, D. H., Adams, B. J., & Fierer, N. Elevational constraints on the composition and genomic attributes of microbial communities in Antarctic soils. Msystems, 7(1), (2022): e01330-21, https://doi.org/10.1128/msystems.01330-21.The inland soils found on the Antarctic continent represent one of the more challenging environments for microbial life on Earth. Nevertheless, Antarctic soils harbor unique bacterial and archaeal (prokaryotic) communities able to cope with extremely cold and dry conditions. These communities are not homogeneous, and the taxonomic composition and functional capabilities (genomic attributes) of these communities across environmental gradients remain largely undetermined. We analyzed the prokaryotic communities in soil samples collected from across the Shackleton Glacier region of Antarctica by coupling quantitative PCR, marker gene amplicon sequencing, and shotgun metagenomic sequencing. We found that elevation was the dominant factor explaining differences in the structures of the soil prokaryotic communities, with the drier and saltier soils found at higher elevations harboring less diverse communities and unique assemblages of cooccurring taxa. The higher-elevation soil communities also had lower maximum potential growth rates (as inferred from metagenome-based estimates of codon usage bias) and an overrepresentation of genes associated with trace gas metabolism. Together, these results highlight the utility of assessing community shifts across pronounced environmental gradients to improve our understanding of the microbial diversity found in Antarctic soils and the strategies used by soil microbes to persist at the limits of habitability.Geospatial support for this work was provided by the Polar Geospatial Center under NSF-OPP awards 1043681 and 155969. This work was supported by grants from the U.S. National Science Foundation Office of Polar Programs (1341629, 1341629, 1341736, and 1637708 to B.J.A., N.F., W.B.L., and D.H.W.), with additional support provided to N.B.D. from the University of Colorado Department of Ecology and Evolutionary Biology

Genetic diversity among populations of Antarctic springtails (Collembola) within the Mackay Glacier ecotone

Climate changes are likely to have major influences on the distribution and abundance of Antarctic terrestrial biota. To assess arthropod distribution and diversity within the Ross Sea region, we examined mitochondrial DNA (COI) sequences for three currently recognized species of springtail (Collembola) collected from sites in the vicinity, and to the north of, the Mackay Glacier (77°S). This area acts as a transition between two biogeographic regions (northern and southern Victoria Land). We found populations of highly divergent individuals (5%–11.3% intraspecific sequence divergence) for each of the three putative springtail species, suggesting the possibility of cryptic diversity. Based on molecular clock estimates, these divergent lineages are likely to have been isolated for 3–5 million years. It was during this time that the Western Antarctic Ice Sheet (WAIS) was likely to have completely collapsed, potentially facilitating springtail dispersal via rafting on running waters and open seaways. The reformation of the WAIS would have isolated newly established populations, with subsequent dispersal restricted by glaciers and ice-covered areas. Given the currently limited distributions for these genetically divergent populations, any future changes in species’ distributions can be easily tracked through the DNA barcoding of springtails from within the Mackay Glacier ecotone

The soil geochemistry in the Beardmore Glacier Region, Antarctica: Implications for terrestrial ecosystem history

Although most models suggest continental Antarctica was covered by ice during the Last Glacial Maximum (LGM) it has been speculated that endemic species of soil invertebrates could have survived the Pleistocene at high elevation habitats protruding above the ice sheets. We analyzed a series of soil samples from different elevations at three locations along the Beardmore Glacier in the Transantarctic Mountains (in order of increasing elevation): Ebony Ridge (ER), Cloudmaker (CM), and Meyer Desert (MD). Geochemical analyses show the MD soils, which were exposed during the LGM, were the least weathered compared to lower elevations, and also had the highest total dissolved solids (TDS). MD soils are dominated by nitrate salts (NO₃/Cl ratios >10) that can be observed in SEM images. High δ¹⁷O and δ¹⁸O values of the nitrate indicate that its source is solely of atmospheric origin. It is suggested that nitrate concentrations in the soil may be utilized to determine a relative “wetting age” to better assess invertebrate habitat suitability. The highest elevation sites at MD have been exposed and accumulating salts for the longest times, and because of the salt accumulations, they were not suitable as invertebrate refugia during the LGM

Defining the concept of ‘tick repellency’ in veterinary medicine

Although widely used, the term repellency needs to be employed with care when applied to ticks and other periodic or permanent ectoparasites. Repellency has classically been used to describe the effects of a substance that causes a flying arthropod to make oriented movements away from its source. However, for crawling arthropods such as ticks, the term commonly subsumes a range of effects that include arthropod irritation and consequent avoiding or leaving the host, failing to attach, to bite, or to feed. The objective of the present article is to highlight the need for clarity, to propose consensus descriptions and methods for the evaluation of various effects on ticks caused by chemical substances