Conformational Heterogeneity of a Leucine Enkephalin Analog in Aqueous Solution and SDS Micelles: Comparison of Time- Resolved FRET and Molecular Dynamics Simulations

We have undertaken time-resolved Förster resonance energy transfer (FRET) and molecular dynamics simulations to analyze conformations and conformational heterogeneity of an analog of leucine enkephalin in solution and in the presence of SDS micelles. Enkephalins are opioid pentapeptides that interact with opioid receptors in the central nervous system. We used timecorrelated single-photon counting to detect energy transfer between the N-terminal tyrosine and a tryptophan residue substituted for phenylalanine at the 4 position. FRET from Tyr to Trp was measured over a temperature range from 5°C to 55°C in aqueous solution. By taking into account Tyr rotamer interconversion rates measured previously, we determined average distances between Tyr and Trp for the two populated rotameric conformations of Tyr. Molecular dynamics simulations (100 ns) support this analysis and indicate extensive conformational heterogeneity. The simulations also predict that the FRET orientational factor is correlated with the Tyr-Trp separation. Failure to account for the correlation between orientation and distance results in errors that appear to be largely offset in YGGWL by a weighting bias inherent in the R−6 dependence of the energy-transfer rate. The Tyr lifetimes decrease upon titration of the peptides with SDS, indicating formation of compact conformations of the peptide in the micelle environment. This result is consistent with the conjecture that the lipid environment may induce formation of bioactive conformations of the peptide

Influence of temperature and viscosity on anthracene rotational diffusion in organic solvents: Molecular dynamics simulations and fluorescence anisotropy study

This is the publisher's version, also available electronically from http://scitation.aip.org/content/aip/journal/jcp/107/21/10.1063/1.475172.Molecular dynamics simulations and fluorescenceanisotropy decay measurements are used to investigate the rotational diffusion of anthracene in two organic solvents—cyclohexane and 2-propanol—at several temperatures. Molecular dynamics simulations of 1 ns length were performed for anthracene in cyclohexane (at 280, 296, and 310 K) and in 2-propanol (at 296 K). The calculated time constants for reorientation of the short in-plane axis were 7–9 and 11–16 ps at 296 K in cyclohexane and 2-propanol, respectively, in excellent agreement with corresponding fluorescence depolarization measurements of 8 and 14 ps. The measured rotational reorientation times and the calculated average rotational diffusion coefficients varied in accord with Debye–Stokes–Einstein theory. Their magnitudes were close to values predicted for an ellipsoid of shape and size equivalent to an anthracene molecule, and exhibited predictable variation with external conditions—increasing with temperature and decreasing with solventviscosity. However, analysis of the calculated rotational diffusion coefficients for the individual molecular axes gave a more complex picture. The diffusion was highly anisotropic and changes in temperature and solvent type led to nonuniform variation of the diffusion coefficients. The nature of these changes was rationalized based on analysis of variation of solvation patterns with temperature and solvent

Readability of internet based patient information for Radiotherapy Patients

Information is key to patient informed choice and the internet is currently a major source of health information for adults in the UK. In order for the users to make use of the information it must be presented in a way that the user can understand. This depends on a number of factors one being that the document is written at the right level to be understood by the reader, readability. The aim of this study was to assess the readability of radiotherapy-related documents on the internet and compare their levels to published norms. An internet search was undertaken using Google, to identify UK-based literature. Once identified documents were downloaded into Word and cleaned of punctuation other than that at the end of the sentence, documents were then analysed by the software package Readability Studio. Documents tended to be written at too high a reading level, but the reading level had improved from a similar study conducted in 2006. The level of readability appears to show a relationship to the use of passive voice, which was very variable in the sample collected and reduction in the use of passive voice could help with the readability of the information

Dynamic elements and kinetics: Most favorable conformations of peptides in solution with measurements and simulations

This article may be downloaded for personal use only. Any other use requires prior permission of the author and AIP Publishing. This article appeared inJ. Chem. Phys. 151, 225102 (2019); doi: 10.1063/1.5131782 and may be found at https://aip.scitation.org/doi/10.1063/1.5131782.Small peptides in solution adopt a specific morphology as they function. It is of fundamental interest to examine the structural properties of these small biomolecules in solution and observe how they transition from one conformation to another and form functional structures. In this study, we have examined the structural properties of a simple dipeptide and a five-residue peptide with the application of far-UV circular dichroism (CD) spectroscopy as a function of temperature, fluorescence anisotropy, and all-atom molecular dynamics simulation. Analysis of the temperature dependent CD spectra shows that the simplest dipeptide N-acetyl-tryptophan-amide (NATA) adopts helical, beta sheet, and random coil conformations. At room temperature, NATA is found to have 5% alpha-helical, 37% beta sheet, and 58% random coil conformations. To our knowledge, this type of structural content in a simplest dipeptide has not been observed earlier. The pentapeptide (WK5) is found to have four major secondary structural elements with 8% 310 helix, 14% poly-L-proline II, 8% beta sheet, and 14% turns. A 56% unordered structural population is also present for WK5. The presence of a significant population of 310 helix in a simple pentapeptide is rarely observed. Fluorescence anisotropy decay (FAD) measurements yielded reorientation times of 45 ps for NATA and 120 ps for WK5. The fluorescence anisotropy decay measurements reveal the size differences between the two peptides, NATA and WK5, with possible contributions from differences in shape, interactions with the environment, and conformational dynamics. All-atom molecular dynamics simulations were used to model the structures and motions of these two systems in solution. The predicted structures sampled by both peptides qualitatively agree with the experimental findings. Kinetic modeling with optimal dimensionality reduction suggests that the slowest dynamic processes in the dipeptide involve sidechain transitions occurring on a 1 ns timescale. The kinetics in the pentapeptide monitors the formation of a distorted helical structure from an extended conformation on a timescale of 10 ns. Modeling of the fluorescence anisotropy decay is found to be in good agreement with the measured data and correlates with the main contributions of the measured reorientation times to individual conformers, which we define as dynamic elements. In NATA, the FAD can be well represented as a sum of contributions from representative conformers. This is not the case in WK5, where our analysis suggests the existence of coupling between conformational dynamics and global tumbling. The current study involving detailed experimental measurements and atomically detailed modeling reveals the existence of specific secondary structural elements and novel dynamical features even in the simplest peptide systems

Uncertainty in hydrological signatures for gauged and ungauged catchments

Reliable information about hydrological behavior is needed for water‐resource management and scientific investigations. Hydrological signatures quantify catchment behavior as index values, and can be predicted for ungauged catchments using a regionalization procedure. The prediction reliability is affected by data uncertainties for the gauged catchments used in prediction and by uncertainties in the regionalization procedure. We quantified signature uncertainty stemming from discharge data uncertainty for 43 UK catchments and propagated these uncertainties in signature regionalization, while accounting for regionalization uncertainty with a weighted‐pooling‐group approach. Discharge uncertainty was estimated using Monte Carlo sampling of multiple feasible rating curves. For each sampled rating curve, a discharge time series was calculated and used in deriving the gauged signature uncertainty distribution. We found that the gauged uncertainty varied with signature type, local measurement conditions and catchment behavior, with the highest uncertainties (median relative uncertainty ±30–40% across all catchments) for signatures measuring high‐ and low‐flow magnitude and dynamics. Our regionalization method allowed assessing the role and relative magnitudes of the gauged and regionalized uncertainty sources in shaping the signature uncertainty distributions predicted for catchments treated as ungauged. We found that (1) if the gauged uncertainties were neglected there was a clear risk of overconditioning the regionalization inference, e.g., by attributing catchment differences resulting from gauged uncertainty to differences in catchment behavior, and (2) uncertainty in the regionalization results was lower for signatures measuring flow distribution (e.g., mean flow) than flow dynamics (e.g., autocorrelation), and for average flows (and then high flows) compared to low flows.Key Points:We quantify impact of data uncertainty on signatures and their regionalizationMedian signature uncertainty ±10–40%, and highly variable across catchmentsNeglecting gauging uncertainty causes overconditioning of regionalizationPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137249/1/wrcr21917-sup-0001-2015WR017635-s01.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137249/2/wrcr21917.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137249/3/wrcr21917_am.pd

‘Building for the Future?’ Government and Industry Responses to the Challenges of Talent Management in China Following the GFC

China suffered minimal fallout from the global financial crisis due to its burgeoning economy and ‘socialism with Chinese characteristics’ political strategy. However, despite this, its industries face enormous human resource management (HRM) challenges associated with the country's rapid economic growth. Principal amongst these HRM challenges is the need to attract and retain crucial talent. It is likely that if Chinese industry is unsuccessful in these endeavours, the future economic growth of China may be stalled, resulting in more serious long-term outcomes. This paper explores these challenges together with some possible solutions and future research directions

Quantifying simulator discrepancy in discrete-time dynamical simulators

When making predictions with complex simulators it can be important to quantify the various sources of uncertainty. Errors in the structural specification of the simulator, for example due to missing processes or incorrect mathematical specification, can be a major source of uncertainty, but are often ignored. We introduce a methodology for inferring the discrepancy between the simulator and the system in discrete-time dynamical simulators. We assume a structural form for the discrepancy function, and show how to infer the maximum-likelihood parameter estimates using a particle filter embedded within a Monte Carlo expectation maximization (MCEM) algorithm. We illustrate the method on a conceptual rainfall-runoff simulator (logSPM) used to model the Abercrombie catchment in Australia. We assess the simulator and discrepancy model on the basis of their predictive performance using proper scoring rules. This article has supplementary material online