Relative energetics of acetyl-histidine protomers with and without Zn²⁺ and a benchmark of energy methods

We studied acetylhistidine (AcH), bare or microsolvated with a zinc cation by simulations in isolation. First, a global search for minima of the potential energy surface combining both, empirical and first-principles methods, is performed individually for either one of five possible protonation states. Comparing the most stable structures between tautomeric forms of negatively charged AcH shows a clear preference for conformers with the neutral imidazole ring protonated at the N-epsilon-2 atom. When adding a zinc cation to the system, the situation is reversed and N-delta-1-protonated structures are energetically more favorable. Obtained minima structures then served as basis for a benchmark study to examine the goodness of commonly applied levels of theory, i.e. force fields, semi-empirical methods, density-functional approximations (DFA), and wavefunction-based methods with respect to high-level coupled-cluster calculations, i.e. the DLPNO-CCSD(T) method. All tested force fields and semi-empirical methods show a poor performance in reproducing the energy hierarchies of conformers, in particular of systems involving the zinc cation. Meta-GGA, hybrid, double hybrid DFAs, and the MP2 method are able to describe the energetics of the reference method within chemical accuracy, i.e. with a mean absolute error of less than 1kcal/mol. Best performance is found for the double hybrid DFA B3LYP+XYG3 with a mean absolute error of 0.7 kcal/mol and a maximum error of 1.8 kcal/mol. While MP2 performs similarly as B3LYP+XYG3, computational costs, i.e. timings, are increased by a factor of 4 in comparison due to the large basis sets required for accurate results

Going clean: structure and dynamics of peptides in the gas phase and paths to solvation

The gas phase is an artificial environment for biomolecules that has gained much attention both experimentally and theoretically due to its unique characteristic of providing a clean room environment for the comparison between theory and experiment. In this review we give an overview mainly on first-principles simulations of isolated peptides and the initial steps of their interactions with ions and solvent molecules: a bottom up approach to the complexity of biological environments. We focus on the accuracy of different methods to explore the conformational space, the connections between theory and experiment regarding collision cross section evaluations and (anharmonic) vibrational spectra, and the challenges faced in this field

Better force fields start with better data: A data set of cation dipeptide interactions

We present a data set from a first-principles study of amino-methylated and acetylated (capped) dipeptides of the 20 proteinogenic amino acids – including alternative possible side chain protonation states and their interactions with selected divalent cations (Ca2+, Mg2+ and Ba2+). The data covers 21,909 stationary points on the respective potential-energy surfaces in a wide relative energy range of up to 4 eV (390 kJ/mol). Relevant properties of interest, like partial charges, were derived for the conformers. The motivation was to provide a solid data basis for force field parameterization and further applications like machine learning or benchmarking. In particular the process of creating all this data on the same first-principles footing, i.e. density-functional theory calculations employing the generalized gradient approximation with a van der Waals correction, makes this data suitable for first principles data-driven force field development. To make the data accessible across domain borders and to machines, we formalized the metadata in an ontology

On the use of robust regression in econometrics

The use of robust regression estimators has gained popularity among applied econometricians. The main argument invoked to justify the use of the robust estimators is that they provide efficiency gains in the presence of outliers or non-normal errors. Unfortunately, most practitioners seem to be unaware of the fact that heteroskedastic and skewed errors can dramatically affect the properties of these estimators. In this paper we reconsider the interpretation of the specific robust estimator that has become popular in applied econometrics, and conclude that its use in this context cannot be generally recommended

Evolution of nonstop, no-go and nonsense-mediated mRNA decay and their termination factor-derived components

<p>Abstract</p> <p>Background</p> <p>Members of the eukaryote/archaea specific eRF1 and eRF3 protein families have central roles in translation termination. They are also central to various mRNA surveillance mechanisms, together with the eRF1 paralogue Dom34p and the eRF3 paralogues Hbs1p and Ski7p. We have examined the evolution of eRF1 and eRF3 families using sequence similarity searching, multiple sequence alignment and phylogenetic analysis.</p> <p>Results</p> <p>Extensive BLAST searches confirm that Hbs1p and eRF3 are limited to eukaryotes, while Dom34p and eRF1 (a/eRF1) are universal in eukaryotes and archaea. Ski7p appears to be restricted to a subset of <it>Saccharomyces </it>species. Alignments show that Dom34p does not possess the characteristic class-1 RF minidomains GGQ, NIKS and YXCXXXF, in line with recent crystallographic analysis of Dom34p. Phylogenetic trees of the protein families allow us to reconstruct the evolution of mRNA surveillance mechanisms mediated by these proteins in eukaryotes and archaea.</p> <p>Conclusion</p> <p>We propose that the last common ancestor of eukaryotes and archaea possessed Dom34p-mediated no-go decay (NGD). This ancestral Dom34p may or may not have required a trGTPase, mostly like a/eEF1A, for its delivery to the ribosome. At an early stage in eukaryotic evolution, eEF1A was duplicated, giving rise to eRF3, which was recruited for translation termination, interacting with eRF1. eRF3 evolved nonsense-mediated decay (NMD) activity either before or after it was again duplicated, giving rise to Hbs1p, which we propose was recruited to assist eDom34p in eukaryotic NGD. Finally, a third duplication within ascomycete yeast gave rise to Ski7p, which may have become specialised for a subset of existing Hbs1p functions in non-stop decay (NSD). We suggest Ski7p-mediated NSD may be a specialised mechanism for counteracting the effects of increased stop codon read-through caused by prion-domain [PSI+] mediated eRF3 precipitation.</p

FAIR Practices in Europe

Institutions driving fundamental research at the cutting edge such as for example from the Max Planck Society (MPS) took steps to optimize data management and stewardship to be able to address new scientific questions. In this paper we selected three institutes from the MPS from the areas of humanities, environmental sciences and natural sciences as examples to indicate the efforts to integrate large amounts of data from collaborators worldwide to create a data space that is ready to be exploited to get new insights based on data intensive science methods. For this integration the typical challenges of fragmentation, bad quality and also social differences had to be overcome. In all three cases, well-managed repositories that are driven by the scientific needs and harmonization principles that have been agreed upon in the community were the core pillars. It is not surprising that these principles are very much aligned with what have now become the FAIR principles. The FAIR principles confirm the correctness of earlier decisions and their clear formulation identified the gaps which the projects need to address

Photodissociation of Conformer-Selected Ubiquitin Ions Reveals Site-Specific Cis/Trans Isomerization of Proline Peptide Bonds

Ultraviolet photodissociation (UVPD) of gas-phase proteins has attracted increased attention in recent years. This growing interest is largely based on the fact that, in contrast to slow heating techniques such as collision induced dissociation (CID), the cleavage propensity after absorption of UV light is distributed over the entire protein sequence, which can lead to a very high sequence coverage as required in typical top-down proteomics applications. However, in the gas phase, proteins can adopt a multitude of distinct and sometimes coexisting conformations, and it is not clear how this three-dimensional structure affects the UVPD fragmentation behavior. Using ion mobility–UVPD–mass spectrometry in conjunction with molecular dynamics simulations, we provide the first experimental evidence that UVPD is sensitive to the higher order structure of gas-phase proteins. Distinct UVPD spectra were obtained for different extended conformations of 11+ ubiquitin ions. Assignment of the fragments showed that the majority of differences arise from cis/trans isomerization of one particular proline peptide bond. Seen from a broader perspective, these data highlight the potential of UVPD to be used for the structural analysis of proteins in the gas phas

The SQM/COSMO filter: reliable native pose identification based on the quantum-mechanical description of protein–ligand interactions and implicit COSMO solvation

Current virtual screening tools are fast, but reliable scoring is elusive. Here, we present the "SQM/COSMO filter", a novel scoring function featuring a quantitative semiempirical quantum mechanical (SQM) description of all types of noncovalent interactions coupled with implicit COSMO solvation. We show unequivocally that it outperforms eight widely used scoring functions. The accuracy and chemical generality of the SQM/COSMO filter make it a perfect tool for late stages of virtual screening

Impact of anion polarizability on ion pairing in microhydrated salt clusters

Despite longstanding interest in the mechanism of salt dissolution in aqueous media, a molecular level understanding remains incomplete. Here, cryogenic ion trap vibrational action spectroscopy is combined with electronic structure calculations to track salt hydration in a gas phase model system one water molecule at a time. The infrared photodissociation spectra of microhydrated lithium dihalide anions [LiXX′(H2O)n]- (XX′ = I2, ClI and Cl2; n = 1–3) in the OH stretching region (3800–2800 cm-1) provide a detailed picture of how anion polarizability influences the competition among ion–ion, ion–water and water–water interactions. While exclusively contact ion pairs are observed for n = 1, the formation of solvent-shared ion pairs, identified by markedly red-shifted OH stretching bands (-1), originating from the bridging water molecules, is favored already for n = 2. For n = 3, Li+ reaches its maximum coordination number of four only in [LiI2(H2O)3]-, in accordance with the hard and soft Lewis acid and base principle. Water–water hydrogen bond formation leads to a different solvent-shared ion pair motif in [LiI2(H2O)3]- and network formation even restabilizes the contact ion pair motif in [LiCl2(H2O)3]-. Structural assignments are exclusively possible after the consideration of anharmonic effects. Molecular dynamics simulations confirm that the significance of large amplitude motion (of the water molecules) increases with increasing anion polarizability and that needs to be considered already at cryogenic temperatures

Horses for courses: subject differences in the chances of securing different types of graduate jobs in the UK

Analysis of the 2010/11 Longitudinal Destinations of Leavers from Higher Education survey shows that overly-simplistic conceptions of graduate success underestimate the value of obtaining a degree in some subjects. Using a skills-based classification of graduate jobs the research finds that maths and vocationally-oriented subjects associated with higher earnings returns (Belfield et al., 2018a, 2018b) - engineering, architecture, computer science and nursing - increase the chances of having an 'Expert' job compared to the average for all graduates. However, more generalist subjects that have been linked with lower earnings such as creative arts, languages and mass communication and documentation are better for accessing graduate jobs where creativity and ability to communicate is key. The research demonstrates the value of using a more nuanced conception of graduate jobs and shows that debate about the value of higher education needs to move away from a narrow focus on earnings