This study presents a unique data set that combines measurements of velocities and void fraction under an unsteady deep water plunging breaker in a laboratory. Flow properties in the aerated crest region of the breaking wave were measured using modified particle image velocimetry (PIV) and bubble image velocimetry (BIV). Results show that the maximum velocity in the plunging breaker reached 1.68C at the first impingement of the overturning water jet with C being the phase speed of the primary breaking wave, while the maximum velocity reached 2.14C at the beginning of the first splash-up. A similarity profile of void fraction was found in the successive impinging and splash-up rollers. In the highly foamy splashing roller, the increase of turbulent level and vorticity level were strongly correlated with the increase of void fraction when the range of void fraction was between 0 and 0.4 (from the trough level to approximately the center of the roller). The levels became constant when void fraction was greater than 0.5. The mass flux, momentum flux, kinetic energy, potential energy, and total energy were computed and compared with and without the void fraction being accounted for. The results show that all the mean and turbulence properties related to the air-water mixture are considerably overestimated unless void fraction is considered. When including the density variation due to the air bubbles, the wave energy dissipated exponentially a short distance after breaking; about 54% and 85% of the total energy dissipated within one and two wavelengths beyond the breaking wave impingement point, respectively.

Advances in high-throughput screening now enable the rapid discovery of bioactive small molecules, but these primary hits almost always exhibit modest potency. We report a strategy for the transformation of these hits into much more potent inhibitors without compound optimization. Appending a derivative of Ru(II)(tris-bipyridyl)2+, an efficient photosensitizer of singlet oxygen production, to synthetic protein-binding compounds results in highly potent and specific target protein inactivation upon irradiation with visible light.

The 26S proteasome is an approximately 2.5 MDa multi-catalytic protease complex that is responsible for most non-lysosomal protein degradation in eukaryotic cells. It is composed of a barrel-like catalytic 20S core particle (CP) that consists of four stacked heteroheptameric rings capped on each side by a 19S regulatory particle (RP) (Figure 1), 1 which contains a putative hetero-hexameric ring of ATPases (Rpt1-6) as well as several other proteins. The RP binds polyubiquitylated proteins, unfolds them, and feeds the polypeptide chain into the interior of the barrel where the proteins are degraded into small peptides. 2 Inhibition of the 20S CP proteolytic activity has emerged as an attractive pharmacological target for cancer and inflammatory diseases 3,4 as well as useful as mechanistic probes of proteasome function in a variety of biological processes. 3 Recently, a number of pioneering studies have revealed that stimulating proteasome-mediated proteolysis is but one of several activities of the Rpt proteins. It is now clear that these ATPases play non-proteolytic roles in RNA polymerase II transcription, DNA repair, structural modification of chromatin and other nuclear processes. 5-10 Therefore, pharmacological inhibitors of the proteasomal ATPases (Rpts) would be of great interest. Here we report the isolation of the first compound of this type from a library of nucleoside-capped peptoids. We show that this peptoid derivative inhibits the protein unfolding activity of the Rpt proteins in vitro and inhibits the proteasome activity in living cells.A "one bead one compound" peptoid library was constructed by split and pool synthesis (see Supporting Information Figure S1). 11 Each peptoid molecule was capped with a purine analogue ( Figure 2A) in hope of biasing the library toward targeting one of the ATPases. The theoretical diversity of the library was 8 5 (32 768 compounds). Approximately 100 000 beads, representing about 3-fold coverage of the library, were used in the screen for compounds that bind to the proteasome. The screen employed a whole cell extract 12 prepared from a yeast strain that expressed a FLAG-tagged 4 proteasome subunit (one of the 20S proteins). The beads were exposed to the extract, washed thoroughly (see Supporting Information), probed with anti-FLAG monoclonal antibody, and then washed again. Finally, putative proteasomebinding peptoids were visualized by addition of a secondary antiIgG antibody labeled with red-emitting quantum dots. 13 Three beads evinced an obvious red halo, consistent with retention of the quantum-dot-conjugated secondary antibody ( Figure 2B). Note that the library had been prescreened to eliminate peptoids that bound directly to the antibodies or the quantum dot before exposing it to the yeast extract. Edman degradation revealed that all three hits were identical, indicating the presence of a single proteasome-binding peptoid in the library with sufficient affinity and specificity to register under these relatively demanding conditions. We called this compound ...

No abstract

Background: Amot130 regulates cell differentiation and growth signaling. Results: Amot130 binds and activates overexpressed AIP4 to ubiquitinate Amot130 and YAP resulting in Amot130 stabilization and YAP degradation. Conclusion: Amot130 and AIP4 cooperatively inhibit YAP and cell growth. Significance: A mechanism is described whereby Amot130 directs AIP4 to potentially suppress tumor cell growth.

Do you copy? A cell‐permeable synthetic transcription factor mimic composed of a DNA‐binding hairpin polyamide and an activation‐domain‐like peptoid can turn on gene transcription in living cells.

No abstract

Molecular docking is widely used to obtain binding modes and binding affinities of a molecule to a given target protein. Despite considerable efforts, however, prediction of both properties by docking remains challenging mainly due to protein’s structural flexibility and inaccuracy of scoring functions. Here, an integrated approach has been developed to improve the accuracy of binding mode and affinity prediction, and tested for small molecule MDM2 and MDMX antagonists. In this approach, initial candidate models selected from docking are subjected to equilibration MD simulations to further filter the models. Free energy perturbation molecular dynamics (FEP/MD) simulations are then applied to the filtered ligand models to enhance the ability in predicting the near-native ligand conformation. The calculated binding free energies for MDM2 complexes are overestimated compared to experimental measurements mainly due to the difficulties in sampling highly flexible apo-MDM2. Nonetheless, the FEP/MD binding free energy calculations are more promising for discriminating binders from nonbinders than docking scores. In particular, the comparison between the MDM2 and MDMX results suggests that apo-MDMX has lower flexibility than apo-MDM2. In addition, the FEP/MD calculations provide detailed information on the different energetic contributions to ligand binding, leading to a better understanding of the sensitivity and specificity of protein-ligand interactions.