Tautomeric Effect of Histidine on the Monomeric Structure of Amyloid β‑Peptide(1–42)

Tautomeric state of histidine is one of the factors that influence the structural and aggregation properties of amyloid β (Aβ)-peptide in neutral state. It is worth it to uncover the monomeric properties of Aβ(1–42) peptide in comparison with Aβ(1–40) peptide. Our replica-exchange molecular dynamics simulations results show that the sheet content of each tautomeric isomer in Aβ(1–42) monomer is slightly higher than that in Aβ(1–40) monomer except His6­(δ)-His13­(δ)-His14­(δ) (δδδ) isomer, implying higher aggregation tendency in Aβ­(1–42), which is in agreement with previous experimental and theoretical studies. Further analysis indicates that (εεε), (εδε), (εδδ), and (δδε) isomers prefer sheet conformation although they are in nondominating states. Particularly, it is confirmed that antiparallel β-sheets of (εδδ) were formed at K16-E22 (22.0–43.9%), N27-A30 except G29 (21.9–40.2%), and M35-I41 except G37 (24.1–43.4%). Furthermore, (εδδ) may be the easiest one to overcome structural transformation due to nonobstructing interactions between K16 and/or L17 and histidine residues. The current study will help to understand the tautomeric effect of Aβ(1–42) peptide to overcome Alzheimer’s disease

Tautomeric Effect of Histidine on the Monomeric Structure of Amyloid β‑Peptide(1–40)

Histidine state (deprotonated, neutral, and protonated) is considered an important factor influencing the structural properties and aggregation mechanisms in amyloid β-peptides (Aβ), which are associated with the pathogenesis of Alzheimer’s disease. Understanding the structural properties and aggregation mechanisms is a great challenge because two forms (the N^ε–H or N^δ–H tautomer) can exist in the free neutral state of histidine. Here, replica-exchange molecular dynamics simulation was performed to elucidate the changes in structure and the mechanism of aggregation influenced by tautomeric behaviors of histidine in Aβ(1–40). Our results show that sheet-dominating conformations can be found in the His6­(δ)–His13­(δ)–His14­(δ) (δδδ) isomer with significant antiparallel sheet structures between R5–D7 and L34–G38, as well as between L17–F20 and L34–G38, implying that a new aggregation mechanism may exist to promote the generation of oligomers and/or aggregates. This work is helpful in understanding the fundamental tautomeric behaviors of neutral histidine in the process of aggregation

Zn²⁺ Effect on Structure and Residual Hydrophobicity of Amyloid β‑Peptide Monomers

The aggregation of amyloid β-peptide (Aβ peptide) has been associated with the pathogenesis of Alzheimer’s disease (AD). In the present study, we aimed to disclose how Zn²⁺ affects the Aβ aggregation in detail. Thus, molecular dynamics simulation was implemented to elucidate the changes of structure and residual hydrophobicity upon Zn²⁺ coordination. Our results show that Zn²⁺ can strongly influence the structural properties of Aβ40 and Aβ42 by reducing helical formation and increasing turn formation to expose the hydrophobic regions. Furthermore, hydrophobicity of Zn²⁺-Aβ40 and Zn²⁺-Aβ42 was much higher than that of each monomer, since Zn²⁺ binding can significantly influence the hydrophilic domains of Aβ. The further analyses indicate that not only four residues (H6, E11, H13, and H14) but also R5, D7, K16, K28, and terminal residues influence hydrophobicity upon Zn²⁺ coordination. Importantly, R5, K16, and K28 play a crucial role to regulate solvation-free energies. This work is helpful to understand the fundamental role of Zn²⁺ in aggregation, which could be useful for further development of new drugs to inhibit Zn²⁺-Aβ aggregation

Ambient Degradation of Perylene Diimide-Based Organic Transistors: Hidden Role of Ozone and External Electric Field

A thorough interpretation on the mechanisms that control the degradation of the electrical performance of organic thin-film transistors (OTFTs) during exposure to ambient environments is still developing. This is particularly true for n-type OTFTs. By performing density functional theory calculations, we have proposed a different degradation pathway of perylene diimide in ambient air. Compared to the most common ambient oxidant, O₃, though seldom considered, can easily react with >CC< in the π-conjugated charge-transfer center forming stable ozonides, which could be the underlying cause for relevant device failures. It is noteworthy that external electric fields which are ubiquitous while often overlooked in electronic devices can either accelerate or hamper the degradation process depending on the field direction. This finding underlines that in a rigid device configuration where electrodes are largely fixed, the way the molecules align on the substrate is pivotal to their ambient stability. Among the tested substituents, cyanation at the periphery of the perylene core resists O₃/O₂ attack and favors electron transport by lowering the internal reorganization energy. This work constitutes the first step on understanding the interplay of interfacial oxidations and molecular charge-transport properties toward modeling the bulk electrical performance

Bioinspired Synthesis of Chiral 3,4-Dihydropyranones via S‑to‑O Acyl-Transfer Reactions

A bioinspired synthesis of chiral 3,4-dihydropyranones via S-to-O acyl-transfer reactions is described. Asymmetric Michael addition–lactonization reactions of β,γ-unsaturated α-keto esters with thioesters are catalyzed by proline-derived urea, providing 3,4-dihydropyranones and spiro-3,4-dihydrocoumarin-fused 3′,4′-dihydropyranones in high yield (up to 94%) with excellent stereoselectivities (up to >20:1 dr, 99% <i>ee</i>) under catalyst loadings as low as 1 mol %

PLK1-Targeted Fluorescent Tumor Imaging with High Signal-to-Background Ratio

As significantly expressed during cell division, polo-like kinase 1 (PLK1) plays crucial roles in numerous mitotic events and has attracted interest as a potential therapeutic marker in oncological drug discovery. We prepared two small molecular fluorescent probes, <b>1</b> and <b>2</b>, conjugated to <b>SBE13</b> (a type II PLK1 inhibitor) to investigate the PLK1-targeted imaging of cancer cells and tumors. Enzymatic docking studies, molecular dynamics simulations, and <i>in vitro</i> and <i>in vivo</i> imaging experiments all supported the selective targeting and visualization of PLK1 expressing cells by probes <b>1</b> and <b>2</b>, and probe <b>2</b> was successfully demonstrated to image PLK1-upregulated tumors with remarkable signal-to-background ratios. These findings represent the first example of small-molecule based fluorescent imaging of tumors using PLK1 as a target, which could provide new avenues for tumor diagnosis and precision therapeutics

Overcoming the Limits of Hypoxia in Photodynamic Therapy: A Carbonic Anhydrase IX-Targeted Approach

A major challenge in photodynamic cancer therapy (PDT) is avoiding PDT-induced hypoxia, which can lead to cancer recurrence and progression through activation of various angiogenic factors and significantly reduce treatment outcomes. Reported here is an acetazolamide (AZ)-conjugated BODIPY photosensitizer (AZ-BPS) designed to mitigate the effects of PDT-based hypoxia by combining the benefits of anti-angiogenesis therapy with PDT. AZ-BPS showed specific affinity to aggressive cancer cells (MDA-MB-231 cells) that overexpress carbonic anhydrase IX (CAIX). It displayed enhanced photocytotoxicity compared to a reference compound, BPS, which is an analogous PDT agent that lacks an acetazolamide unit. AZ-BPS also displayed an enhanced in vivo efficacy in a xenograft mouse tumor regrowth model relative to BPS, an effect attributed to inhibition of tumor angiogenesis by both PDT-induced ROS generation and CAIX knockdown. AZ-BPS was evaluated successfully in clinical samples collected from breast cancer patients. We thus believe that the combined approach described here represents an attractive therapeutic approach to targeting CAIX-overexpressing tumors