This study introduces the "metal-edge-driven" concept and enables the "edge sites on 2D multimetallic nanocatalysts" technique to design versatile heterocatalysts.Free-energy perturbation (FEP) methods are commonly used in drug design to calculate relative binding free energies of different ligands to a common host protein. Alchemical ligand transformations are usually performed in multiple steps which need to be chosen carefully to ensure sufficient phase-space overlap between neighboring states. With one-step or single-step FEP techniques, a single reference state is designed that samples phase-space not only representative of a full transformation but also ideally resembles multiple ligand end states and hence allows for efficient multistate perturbations. Enveloping distribution sampling (EDS) is one example for such a method in which the reference state is created by a mathematical combination of the different ligand end states based on solid statistical mechanics. We have recently proposed a novel approach to EDS which enables efficient barrier crossing between the different end states, termed accelerated EDS (A-EDS). In this work, we further simplify the parametrization of the A-EDS reference state and demonstrate the automated calculation of multiple free-energy differences between different ligands from a single simulation in three different well-described drug design model systems.Peptide methionine sulfoxide reductases (Msrs) are enzymes that repair ROS-damage to sulfur-containing amino acids such as methionine, ensuring functional integrity of cellular proteins. Here we have shown that unlike the majority of pro- and eukaryotic Msrs, the peptide methionine sulfoxide reductase (MsrAB) from the human pathobiont Haemophilus influenzae (Hi) is required for the repair of hypochlorite damage to cell envelope proteins, but more importantly, we were able to demonstrate that MsrAB plays a role in modulating the host immune response to Hi infection. Loss of MsrAB resulted in >1000-fold increase in sensitivity of Hi to HOCl-mediated killing, and also reduced biofilm formation and in-biofilm survival. Expression of msrAB was also induced by hydrogen peroxide and paraquat, but a Hi2019ΔmsrAB strain was not susceptible to killing by these ROS in vitro. Hi2019ΔmsrAB fitness in infection models was low, with a 3-fold reduction in intracellular survival in bronchial epithelial cells, increased susceptibility to neutrophil killing, and a 10-fold reduction in survival in a mouse model of lung infection. Interestingly, infection with Hi2019ΔmsrAB led to specific changes in the antibacterial response of human host cells, with genes encoding antimicrobial peptides (BPI, CAMP) upregulated between 4 and 9 fold compared to infection with Hi2019WT, and reduction in expression of two proteins with antiapoptotic functions (BIRC3, XIAP). Modulation of host immune responses is a novel role for an enzyme of this type and provides first insights into mechanisms by which MsrAB supports Hi survival in vivo.Ultrasonic transducers with large output power have attracted extensive attentions due to their widespread applications in sonar, acoustic levitation, ultrasonic focusing, and so forth. However, the traditional transducer has almost no heat-dissipation capability itself, strictly relying on the assistant coolant system. Introducing high-performance heat-dissipation component is thus highly necessary. Herein, an embedded porcelain radiator component was designed by combining the excellent thermal conductivity of vertically oriented graphene (VG) with the outstanding heat-dissipation characteristics of thermosensitive ceramics, and a new-type transducer with an embedded VG/ceramic-hybrid radiator was constructed to show high heat-dissipation efficiency (up to ∼5 °C/min). Remarkably, prominent heat-dissipation effectiveness (temperature decline of ∼12 °C), enhanced amplitude and vibration uniformity were also achieved for the new-type transducer along with stabilized operating states. This research should pave ways for extending the applications of VG/ceramic hybrids to heat-dissipation scenarios and provide newfangled thoughts for the performance upgrade of multitudinous high-power devices.Understanding molecular principles underlying chaperone-based modulation of kinase client activity is critically important to dissect functions and activation mechanisms of many oncogenic proteins. The recent experimental studies have suggested that phosphorylation sites in the Hsp90 and Cdc37 proteins can serve as conformational communication switches of chaperone regulation and kinase interactions. However, a mechanism of allosteric coupling between phosphorylation sites in the Hsp90 and Cdc37 during client binding is poorly understood, and the molecular signatures underpinning specific roles of phosphorylation sites in the Hsp90 regulation remain unknown. In this work, we employed a combination of evolutionary analysis, coarse-grained molecular simulations together with perturbation-based network modeling and scanning of the unbound and bound Hsp90 and Cdc37 structures to quantify allosteric effects of phosphorylation sites and identify unique signatures that are characteristic for communication switches of kinase-specific client binding. By using network-based metrics of the dynamic intercommunity bridgeness and community centrality, we characterize specific signatures of phosphorylation switches involved in allosteric regulation. Through perturbation-based analysis of the dynamic residue interaction networks, we show that mutations of kinase-specific phosphorylation switches can induce long-range effects and lead to a global rewiring of the allosteric network and signal transmission in the Hsp90-Cdc37-kinase complex. https://www.selleckchem.com/products/nsc16168.html We determine a specific group of phosphorylation sites in the Hsp90 where mutations may have a strong detrimental effect on allosteric interaction network, providing insight into the mechanism of phosphorylation-induced communication switching. The results demonstrate that kinase-specific phosphorylation switches of communications in the Hsp90 may be partly predisposed for their regulatory role based on preexisting allosteric propensities.