Engineering Embden-Meyerhof-Parnas Glycolysis to Generate Noncanonical Reducing Power.

Noncanonical cofactors such as nicotinamide mononucleotide (NMN) supplant the electron-transfer functionality of the natural cofactors, NAD(P), at a lower cost in cell-free biomanufacturing and enable orthogonal electron delivery in whole-cell metabolic engineering. Here, we redesign the high-flux Embden-Meyerhof-Parnas (EMP) glycolytic pathway to generate NMN-based reducing power, by engineering glyceraldehyde-3-phosphate dehydrogenase ( GapN) to utilize NMN. Through iterative rounds of rational design, we discover the variant GapN Penta (P179K-F153S-S330R-I234E-G210Q) with high NMN-dependent activity and GapN Ortho (P179K-F153S-S330R-I234E-G214E) with ~3.

Recent Developments in Free Energy Calculations for Drug Discovery.

The grand challenge in structure-based drug design is achieving accurate prediction of binding free energies. Molecular dynamics (MD) simulations enable modeling of conformational changes critical to the binding process, leading to calculation of thermodynamic quantities involved in estimation of binding affinities. With recent advancements in computing capability and predictive accuracy, MD based virtual screening has progressed from the domain of theoretical attempts to real application in drug development.

Estimating the Roles of Protonation and Electronic Polarization in Absolute Binding Affinity Simulations.

Accurate prediction of binding free energies is critical to streamlining the drug development and protein design process. With the advent of GPU acceleration, absolute alchemical methods, which simulate the removal of ligand electrostatics and van der Waals interactions with the protein, have become routinely accessible and provide a physically rigorous approach that enables full consideration of flexibility and solvent interaction. However, standard explicit solvent simulations are unable to model protonation or electronic polarization changes upon ligand transfer from water to the protein interior, leading to inaccurate prediction of binding affinities for charged molecules.

Are there long-term benefits of experiential, interprofessional education for non-specialists on clinical behaviours and outcomes in diabetes care? A cohort study.

Objectives: Our aim was to assess the impact of an educational initiative for non-specialist, healthcare professionals in the community on the process and quality measures of diabetes care delivered, and changes in their learning experiences and clinical management behaviour in the short and long term.

Setting: Single locality of 26 primary care practices associated with one secondary centre.

Participants: General practitioners and practice nurses managing 4167 patients with diabetes.

Comparative exploration of hydrogen sulfide and water transmembrane free energy surfaces via orthogonal space tempering free energy sampling.

Hydrogen sulfide (H2 S), a commonly known toxic gas compound, possesses unique chemical features that allow this small solute molecule to quickly diffuse through cell membranes. Taking advantage of the recent orthogonal space tempering (OST) method, we comparatively mapped the transmembrane free energy landscapes of H2 S and its structural analogue, water (H2 O), seeking to decipher the molecular determinants that govern their drastically different permeabilities. As revealed by our OST sampling results, in contrast to the highly polar water solute, hydrogen sulfide is evidently amphipathic, and thus inside membrane is favorably localized at the interfacial region, that is, the interface between the polar head-group and nonpolar acyl chain regions.