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Abstract Protein folding has attracted considerable research effort in biochemistry in recent decades. In this work, we explore the potential of quantum computing to solve a simplified version of protein folding. More precisely, we numerically investigate the performance of the Quantum Approximate Optimization Algorithm (QAOA) in sampling low-energy conformations of short peptides. We start by benchmarking the algorithm on an even simpler problem: sampling self-avoiding walks. Motivated by promising results, we then apply the algorithm to a more complete version of protein folding, including a simplified physical potential. In this case, we find less promising results: deep quantum circuits are required to achieve accurate results, and the performance of QAOA can be matched by random sampling up to a small overhead. Overall, these results cast serious doubt on the ability of QAOA to address the protein folding problem in the near term, even in an extremely simplified setting.

Abstract Here, we introduce the ChemicalToolbox, a publicly available web server for performing cheminformatics analysis. The ChemicalToolbox provides an intuitive, graphical interface for common tools for downloading, filtering, visualizing and simulating small molecules and proteins. The ChemicalToolbox is based on Galaxy, an open-source web-based platform which enables accessible and reproducible data analysis. There is already an active Galaxy cheminformatics community using and developing tools. Based on their work, we provide four example workflows which illustrate the capabilities of the ChemicalToolbox, covering assembly of a compound library, hole filling, protein-ligand docking, and construction of a quantitative structure-activity relationship (QSAR) model. These workflows may be modified and combined flexibly, together with the many other tools available, to fit the needs of a particular project. The ChemicalToolbox is hosted on the European Galaxy server and may be accessed via https://cheminformatics.usegalaxy.eu .

This article presents detailed purification procedures for the bromodomains BRD3(1), BRD3(2), BRD4(1), and BRPF1B. In addition we provide crystallization protocols for apo BRD4(1) and BRD4(1) in complex with numerous inhibitors. The protocols described here were successfully applied to obtain affinity data by isothermal titration calorimetry (ITC) and by differential scanning fluorimetry (DSF) as well as structural characterizations of BRD4(1) inhibitor complexes (PDB codes: PDB: 4LYI, PDB: 4LZS, PDB: 4LYW, PDB: 4LZR, PDB: 4LYS, PDB: 5D24, PDB: 5D25, PDB: 5D26, PDB: 5D3H, PDB: 5D3J, PDB: 5D3L, PDB: 5D3N, PDB: 5D3P, PDB: 5D3R, PDB: 5D3S, PDB: 5D3T). These data have been reported previously and are discussed in more detail elsewhere [1,2]. Keywords: Epigenetics, Bromodomains, Drug discovery, X-ray crystallography

P-glycoprotein is capable of effluxing a broad range of cytosolic and membrane penetrating xenobiotic substrates, thus leading to multi-drug resistance and posing a threat for the therapeutic treatment of several diseases, including cancer and central nervous disorders. Herein, a virtual screening campaign followed by experimental validation in Caco-2, MDKCII, and MDKCII mdr1 transfected cell lines has been conducted for the identification of novel phospholipids with P-gp transportation inhibitory activity. Phosphatidylinositol-(1,2-dioctanoyl)-sodium salt (8∶0 PI) was found to significantly inhibit transmembrane P-gp transportation in vitro in a reproducible-, cell line-, and substrate-independent manner. Further tests are needed to determine whether this and other phosphatidylinositols could be co-administered with oral drugs to successfully increase their bioavailability. Moreover, as phosphatidylinositols and phosphoinositides are present in the human diet and are known to play an important role in signal transduction and cell motility, our finding could be of substantial interest for nutrition science as well.

Southern leaf blight (SLB), caused by Bipolaris maydis, poses a significant threat to maize and popcorn production. To understand the molecular mechanisms underlying SLB resistance, we conducted a high-throughput proteomic analysis comparing SLB-resistant (L66) and SLB-susceptible (L51) popcorn genotypes at four and ten days after inoculation (DAI). A total of 717 proteins were identified, with 151 differentially accumulated proteins (DAPs) between the genotypes. Eighteen DAPs exhibited the same regulatory pattern in both the SLB-resistant and SLB-susceptible genotypes at four (R4/S4) and ten (R10/S10) DAI. The protein-protein interaction (PPI) network of differentially accumulated proteins (DAPs) linked to SLB resistance and susceptibility enriched specific metabolic pathways in the SLB response, including photosynthesis, ribosome, ascorbate and aldarate metabolism, glutathione metabolism, and carbon metabolism. Proteins such as photosystem II 11 kD protein (B4FRJ4, PSB27-1), which was up-regulated at both time points (R4/S4 and R10/S10), and 60S acidic ribosomal protein P0 (A0A1D6LEZ7, RPP0B), which was unique to the resistant genotype at both time points (R4 and R10), highlighted the importance of maintaining photosynthetic efficiency and protein synthesis during pathogen attack. Additionally, dehydroascorbate reductase like-3 (B4F817, DHAR3) was consistently up-regulated at both time points in resistant genotypes, emphasizing its role in redox balance and ROS detoxification. In contrast, glyceraldehyde-3-phosphate dehydrogenase (K7UGF5, GAPC2), a glycolytic enzyme, was unique to the susceptible genotype, suggesting its involvement in managing energy metabolism under stress conditions. Our findings suggest that resistance to SLB in popcorn involves a combination of enhanced photosynthetic repair, redox homeostasis, and ribosomal protein activity, providing new potential molecular targets, such as DHAR3 and RPP0B, for genetic improvement in SLB resistance. These results offer valuable insights into breeding programs aimed at developing SLB-resistant popcorn varieties. [ABSTRACT FROM AUTHOR]