化学•材料最新文献

Kinesin-1 is a crucial motor protein that drives the microtubule-based movement of organelles, vital for cellular function and health. Mostly studied at pH 6.9, it moves at approximately 800 nm/s, covers about 1 μm before detaching, and hydrolyzes one ATP per 8 nm step. Given that cellular pH is dynamic and alterations in pH have significant implications for disease, understanding how kinesin-1 functions across different pH levels is crucial. To explore this, we executed single-molecule motility assays paired with precise optical trapping techniques over a pH range of 5.5-9.8. Our results show a consistent positive relationship between increasing pH and the enhanced detachment (off rate) and speed of kinesin-1. Measurements of the nucleotide-dependent off rate show that kinesin-1 exhibits the highest rate of ATPase activity at alkaline pH, while it demonstrates the optimal number of ATP turnover and cargo translocation efficiency at the acidic pH. Physiological pH of 6.9 optimally balances the biophysical activity of kinesin-1, potentially allowing it to function effectively across a range of pH levels. These insights emphasize the crucial role of pH homeostasis in cellular function, highlighting its importance for the precise regulation of motor proteins and efficient intracellular transport.

Human carnosinases (CNs) are Xaa-His metal-ion-activated aminopeptidases that break down bioactive carnosine and other histidine-containing dipeptides. Carnosine is a bioactive peptide found in meat and prevalently used as a supplement and in functional food formulation. Nonetheless, carnosine is digested by CNs rapidly after ingestion. CNs have two isoforms (carnosinase 1 (CN1) and carnosinase 2 (CN2)), where CN1 is the main player in carnosine digestion. CNs contain a catalytic metal ion pair (Zn²⁺ for CN1 and Mn²⁺ for CN2) and two subpockets (S1 and S1' pockets) to accommodate a substrate. Bestatin (BES) has been reported to be active for CN2; however, its inhibition ability for CN1 has remained under debate, because the underlying mechanism remains unclear. This information is important for designing novel CN1-selective inhibitors for proliferating carnosine after ingestion. Thus, molecular dynamics (MD) simulations were performed to explore the binding mechanism of BES to both CN1 and CN2. The binding of BES-CN1 and BES-CN2 was studied in comparison. The results indicated that BES could bind both CNs with different degrees of binding affinity. BES prefers CN2 because: (1) its aryl terminus is trapped by Y197 in an S1 pocket; (ii) the BES polar backbone is firmly bound by catalytic Mn²⁺ ions; and (iii) the S1' pocket can shrink to accommodate the isopropyl end of BES. In contrast, the high mobility of the aryl end and the complete loss of metal-BES interactions in CN1 cause a loose BES binding. Seemingly, polar termini were required for a good CN1 inhibitor.

Herein, a new two-dimensional (2D) Ce-organic frameworks (referred to as SLX-4) was achieved by traditional solvothermal conditions. Initial studies of SLX-4 toward Hantzsch reaction showed that good catalytic activity can be obtained under mild conditions, giving the desired 1,4-dihydropyridines in moderate to high yields. The catalyst could be reused at least 4 times keeping good catalytic activity. Moreover, compared to the previously reported MOFs catalysts for Hantzsch reactions, SLX-4 was stable in most acidic and basic environment, and gave comparable yield.

Alchemical free energy (AFE) calculations can predict binding affinity changes as a function of structural modifications and have become powerful tools for lead optimization and drug discovery. Central to the setup and performance of AFE calculations is the manner of mapping alchemical transformations, known as the topology model. Single, dual, and hybrid topology models have been used with various AFE methods in the field. In recent works, λ-dynamics (λD) free energy calculations, specifically, have preferred the use of a hybrid multiple topology (HMT) for sampling multiple ligand perturbations. In this work, we evaluate a new topology method called ligand overlay (LO) for use with λD-based calculations, including the recently introduced λ-dynamics with a bias-updated Gibbs sampling (LaDyBUGS) approach. LO is a full multiple topology model that allows entire ligands to be sampled and restrained within a λ-dynamics framework. Relative binding free energies were computed with HMT or LO topology models with LaDyBUGS for 45 ligands across five protein benchmark systems. An overall Pearson R correlation of 0.98 and mean unsigned error of 0.32 kcal/mol were observed, suggesting that LO is a viable alternative topology model for λD-based calculations. We discuss the merits of using an HMT or LO model for future ligand studies with λD or LaDyBUGS calculations.

Quantitative characterization of the surface of microdroplets is important to understanding and predicting numerous chemical and physical processes, such as cloud droplet formation and accelerated chemistry in microdroplets. However, it is increasingly appreciated that the surface compositions of microdroplets do not necessarily match those of macroscale solution due to their large surface-area-to-volume (SA-V) ratios and confined volumes. In this work, we explore how both droplet size and composition affect the surface composition of microdroplets by measuring the equilibrium surface tensions of levitated microdroplets containing a single surfactant. We measure the critical micelle concentrations (CMCs) for surfactants of various strengths (macroscale CMC values ranging from 0.02 to 10 mM) in microdroplets with radii ranging from 5 to 25 μm. We accurately model the surface tensions of microdroplets using an equilibrium partitioning model that only requires droplet size and adsorption parameters from macroscale measurements as inputs. Our model predicts that surfactants have an "effective CMC" in microdroplets that is always larger in value than the corresponding macroscale CMC. In some instances, the effective CMC of a surfactant in microdroplets is several orders of magnitude larger than both its macroscale CMC and its macroscale solubility limit. We present a simple expression for the effective CMC in microdroplets that depends on both the macroscale CMC of a surfactant and the SA-V ratio of the microdroplet. Ultimately, our experimental results and model can be used broadly to predict microdroplet surface compositions when investigating surface-driven accelerated chemistry in microdroplets or estimating cloud droplet activation.

Molecules with Hund's rule violations between low-lying singlet and triplet states may enable a new generation of fluorescent emitters. However, only a few classes of molecules are known with this property at the current time. Here, we use a high-throughput screening algorithm of the FORMED database to uncover a class of compounds where the first excited state violates Hund's rule. We examine this class of bridged [10]- and [14]annulene perimeters with saturated bridges, and relate them to known conjugated polycyclic systems with Hund's rule violations. Despite the structural similarities with the related class of nonalternant polycyclic hydrocarbons, the mechanism is different in these bridged annulene perimeters. Here, two molecular orbital configurations contribute to each excited state. Consequently, a Hund's rule violation can only be unambiguously assigned based on the symmetry of the lowest excited singlet and triplet states. With several examples of synthetically realistic molecules, the class of bridged [10]- and [14]annulenes thus provides a structural link between the known nonalternant and alternant (azaphenalene) classes of molecules violating Hund's rule. These design principles may open avenues for the identification of new types of molecules where the order of the photophysically relevant first excited singlet and triplet states are inverted.