Constant pH molecular dynamics of proteins in explicit solvent with proton tautomerism

pH is a ubiquitous regulator of biological activity, including protein‐folding, protein‐protein interactions, and enzymatic activity. Existing constant pH molecular dynamics (CPHMD) models that were developed to address questions related to the pH‐dependent properties of proteins are largely based on implicit solvent models. However, implicit solvent models are known to underestimate the desolvation energy of buried charged residues, increasing the error associated with predictions that involve internal ionizable residue that are important in processes like hydrogen transport and electron transfer. Furthermore, discrete water and ions cannot be modeled in implicit solvent, which are important in systems like membrane proteins and ion channels. We report on an explicit solvent constant pH molecular dynamics framework based on multi‐site λ‐dynamics (CPHMD MSλD ). In the CPHMD MSλD framework, we performed seamless alchemical transitions between protonation and tautomeric states using multi‐site λ‐dynamics, and designed novel biasing potentials to ensure that the physical end‐states are predominantly sampled. We show that explicit solvent CPHMD MSλD simulations model realistic pH‐dependent properties of proteins such as the Hen‐Egg White Lysozyme (HEWL), binding domain of 2‐oxoglutarate dehydrogenase (BBL) and N‐terminal domain of ribosomal protein L9 (NTL9), and the p K a predictions are in excellent agreement with experimental values, with a RMSE ranging from 0.72 to 0.84 p K a units. With the recent development of the explicit solvent CPHMD MSλD framework for nucleic acids, accurate modeling of pH‐dependent properties of both major class of biomolecules—proteins and nucleic acids is now possible. Proteins 2014; 82:1319–1331. © 2013 Wiley Periodicals, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/107513/1/prot24499-sup-0002-suppinfo02.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/107513/2/prot24499-sup-0001-suppinfo01.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/107513/3/prot24499.pd

Directions of zero thermal expansion in anisotropic oxides

Figure 13. – Quadric surface visualizing the coefficients of thermal expansion of HfTiO4 at room temperature. Blue is positive, red is negative and yellow represents directions of zero thermal expansion. Oxide materials often have anisotropic crystal structures, which can result in direction-dependent material properties. While they typically have positive coefficients of thermal expansion, it has been observed that some oxide materials can have directions of negative thermal expansion over certain temperature ranges. Such materials, having both positive and negative coefficients of thermal expansion, must also have particular directions in which the thermal expansion is zero. Using the Quadrupole Lamp Furnace (QLF) developed in the Kriven group at the University of Illinois at Urbana Champaign, high-temperature in-situ x-ray diffraction has been performed at the National Synchrotron Light Source II (NSLS II) X-ray powder diffraction beamline (XPD – 28-ID) to track directions of zero thermal expansion in orthorhombic HfTiO4. These results have important implications for the design of composites for high-temperature applications. Please click Additional Files below to see the full abstract

Kansas Dairy Producers\u27 Needs Survey: Reproductive Management on Kansas Dairy Farms

A section of the Kansas Dairy Producers\u27 Needs Survey evaluated needs related to education on reproductive management and the most common reproductive management practices used on Kansas dairy farms. Of the 312 surveys mailed to dairy producers, 70 were returned fully completed. Results indicate that producers need education on the topic of reproduction and that reproductive management practices and herd sizes are related to where farms are located in the state. Consequently, future Extension reproductive management programming should reflect the diversity of Kansas\u27s dairy industry. Moreover, the results presented align with earlier data from a nationwide survey and therefore may have applicability on a national scale

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Copper Chelation via beta-alanine extends lifespan in a C. elegans model of Alzheimer's Disease

The leading hypothesis for Alzheimer's Disease (AD) has traditionally focused on the aggregation of Amyloid-β into amyloid plaques. However, research has yet to definitively prove the role of the amyloid peptide in the pathology of the disease. Given that all therapeutics targeting amyloid plaques have failed in clinical trials, with one exception, there is a need to explore alternative approaches to treatment of this disease. Therefore, we examined other factors that are altered during AD pathogenesis. Many AD patients have dysregulation of metal ions, such as copper and zinc, in addition to accumulation of Amyloid-β. The interaction between Amyloid-β and copper can result in the production of reactive oxygen species (ROS). ROS can cause damage to neurons and surrounding tissues resulting in degradation of the brain. Therefore, our work focuses on disrupting the interaction between Amyloid-β and copper via chelation therapy to prevent ROS formation and, in turn, reduce neurotoxicity. In this study, copper chelation with beta alanine reduced the amount of ROS produced in the brains of C. elegans expressing pan-neuronal Amyloid-β, amino acids 1-42. In response to chelation, the expression of the antioxidant gene, gst-4, was also reduced. Importantly, there was also a positive correlation between copper chelation and increased lifespan in the Amyloid-β expressing C. elegans. Consistent with our previous in vitro work, Amyloid-β expression in vivo was not altered following treatment. Taken together, these results suggest that copper chelation has the potential to serve as an AD therapeutic resulting in increased longevity