Ionic Solution: What Goes Right and Wrong with Continuum Solvation Modeling

Solvent-mediated electrostatic interactions were well recognized to be important in the structure and function of molecular systems. Ionic interaction is an important component in electrostatic interactions, especially in highly charged molecules, such as nucleic acids. Here, we focus on the quality of the widely used Poisson–Boltzmann surface area (PBSA) continuum models in modeling ionic interactions by comparing with both explicit solvent simulations and the experiment. In this work, the molality-dependent chemical potentials for sodium chloride (NaCl) electrolyte were first simulated in the SPC/E explicit solvent. Our high-quality simulation agrees well with both the previous study and the experiment. Given the free-energy simulations in SPC/E as the benchmark, we used the same sets of snapshots collected in the SPC/E solvent model for PBSA free-energy calculations in the hope to achieve the maximum consistency between the two solvent models. Our comparative analysis shows that the molality-dependent chemical potentials of NaCl were reproduced well with both linear PB and nonlinear PB methods, although nonlinear PB agrees better with SPC/E and the experiment. Our free-energy simulations also show that the presence of salt increases the hydrophobic effect in a nonlinear fashion, in qualitative agreement with previous theoretical studies of Onsager and Samaras. However, the lack of molality-dependency in the nonelectrostatics continuum models dramatically reduces the overall quality of PBSA methods in modeling salt-dependent energetics. These analyses point to further improvements needed for more robust modeling of solvent-mediated interactions by the continuum solvation frameworks

Synthesis of All Possible Canonical (3′–5′-Linked) Cyclic Dinucleotides and Evaluation of Riboswitch Interactions and Immune-Stimulatory Effects

The cyclic dinucleotides (CDNs) c-di-GMP, c-di-AMP, and c-AMP-GMP are widely utilized as second messengers in bacteria, where they signal lifestyle changes such as motility and biofilm formation, cell wall and membrane homeostasis, virulence, and exo-electrogenesis. For all known bacterial CDNs, specific riboswitches have been identified that alter gene expression in response to the second messengers. In addition, bacterial CDNs trigger potent immune responses, making them attractive as adjuvants in immune therapies. Besides the three naturally occurring CDNs, seven further CDNs containing canonical 3′–5′-linkages are possible by combining the four natural ribonucleotides. Herein, we have synthesized all ten possible combinations of 3′–5′-linked CDNs. The binding affinity of novel CDNs and GEMM riboswitch variants was assessed utilizing a spinach aptamer fluorescence assay and in-line probing assays. The immune-stimulatory effect of CDNs was evaluated by induction of type I interferons (IFNs), and a novel CDN c-AMP-CMP was identified as a new immune-stimulatory agent

Enhanced Photovoltaic Performance of Tetrazine-Based Small Molecules with Conjugated Side Chains

Two two-dimensional (2D) conjugated tetrazine-based small molecules (SMs), named TBDT­(TTzT)₂ and TBDT­(TTz2T)₂, were newly synthesized for photovoltaic application as donor materials. They employed a molecular backbone of D2-A-D1-A-D2 in which D1 represents an alkylthienyl substituted benzo­[1,2-b:4,5-b′]­dithiophene (BDT) unit, A represents a tetrazine (Tz) unit, and D2 is a bithiophene or terthiophene ending donor unit. These synthesized molecules showed relatively broad light harvesting range and proper energy levels with a fullerene derivative acceptor. Meanwhile, we try to explore how the molecular conjugation influences the opto-electrical properties and photovoltaic performance of the tetrazine-based SM family by making comparison with their non-2D analogues. Experimental results showed that extending main chain conjugated length broadens absorption spectra, whereas side chain conjugation extension leads to larger absorption coefficients, lower highest occupied molecular orbital energy levels, and more favorable blend morphology. The optimized 2D conjugated molecules achieved better device performance with the highest <i>V</i>_oc of 1.03 V and FF of 65.3% after using trace amounts of additive. These results suggested that extending molecular conjugation is a feasible strategy for photovoltaic material design

Identification of New FLT3 Inhibitors That Potently Inhibit AML Cell Lines via an Azo Click-It/Staple-It Approach

Acute myeloid leukemia (AML) is an aggressive malignancy with only a handful of therapeutic options. About 30% of AML patients harbor mutated FLT3 kinase, and thus, this cancer-driver has become a hotly pursued AML target. Herein we report a new class of FLT3 inhibitors, which potently inhibit the proliferation of acute myeloid leukemia (AML) cells at nanomolar concentrations