Potential inhibitors for SARS-CoV-2 Mpro from marine compounds.

Preventing the biological activity of SARS-CoV-2 main protease using natural compounds is of great interest. In this context, using a combination of AutoDock Vina and fast pulling of ligand simulations, eleven marine fungi compounds were identified that probably play as highly potent inhibitors for preventing viral replication. In particular, four compounds including M15 (3-O-(6-O-α-l-arabinopyranosyl)-ß-d-glucopyranosyl-1,4-dimethoxyxanthone), M8 (wailupemycins H), M11 (cottoquinazolines B), and M9 (wailupemycins I) adopted the predicted ligand-binding free energy of -9.87, -9.82, -9.62, and -9.35 kcal mol-1, respectively, whereas the other adopted predicted ligand-binding free energies in the range from -8.54 to -8.94 kcal mol-1. The results were obtained using a combination of Vina and FPL simulations. Notably, although, AutoDock4 adopted higher accurate results in comparison with Vina, Vina is proven to be a more suitable technique for rapidly screening ligand-binding affinity with a large database of compounds since it requires much smaller computing resources. Furthermore, FPL is better than Vina to classify inhibitors upon ROC-AUC analysis.

Interaction of carbohydrate binding module 20 with starch substrates.

CBM20s are starch-binding domains found in many amylolytic enzymes, including glucoamylase, alpha-amylase, beta-amylases, and a new family of starch-active polysaccharide monooxygenases (AA13 PMOs). Previous studies of CBM20-substrate interaction only concerned relatively small or soluble amylose molecules, while amylolytic enzymes often work on extended chains of insoluble starch molecules. In this study, we utilized molecular simulation techniques to gain further insights into the interaction of CBM20 with substrates of various sizes via its two separate binding sites, termed as BdS1 and BdS2. Results show that substrate binding at BdS1 involving two conserved tryptophan residues is about 2-4 kcal mol-1 stronger than that at BdS2. CBM20 exhibits about two-fold higher affinity for helical substrates than for the amylose random coils. The affinity for amylose individual double helices does not depend on the helices' length. At least three parallel double helices are required for optimal binding. The binding affinity for a substrate containing 3 or more double helices is ∼-15 kcal mol-1, which is 2-3 kcal mol-1 larger than that for individual double helices. 100 ns molecular dynamics simulations were carried out for the binding of CBM20 to an extended substrate containing 3 layers of 9 60-unit double helices (A3L). A stable conformation of CBM20-A3L was found at BdS1. However, when CBM20 binds A3L viaBdS2, it moves across the surface of the substrate and does not form a stable complex. MD simulations show that small amylose helices are quickly disrupted upon binding to CBM20. Our results provide some important molecular insights into the interactions of CBM20 with starch substrates, which will serve as the basis for further studies of CBM20-containing enzymes, including AA13 PMOs.

Atomistic investigation of an Iowa Amyloid-ß trimer in aqueous solution.

The self-assembly of Amyloid beta (Aß) peptides are widely accepted to associate with Alzheimer's disease (AD) via several proposed mechanisms. Because Aß oligomers exist in a complicated environment consisting of various forms of Aß, including oligomers, protofibrils, and fibrils, their structure has not been well understood. The negatively charged residue D23 is one of the critical residues of the Aß peptide as it is located in the central hydrophobic domain of the Aß N-terminal and forms a salt-bridge D23-K28, which helps stabilize the loop domain. In the familial Iowa (D23N) mutant, the total net charge of Aß oligomers decreases, resulting in the decrease of electrostatic repulsion between D23N Aß monomers and thus the increase in their self-aggregation rate. In this work, the impact of the D23N mutation on 3Aß11-40 trimer was characterized utilizing temperature replica exchange molecular dynamics (REMD) simulations. Our simulation reveals that D23N mutation significantly enhances the affinity between the constituting chains in the trimer, increases the ß-content (especially in the sequence 21-23), and shifts the ß-strand hydrophobic core from crossing arrangement to parallel arrangement, which is consistent with the increase in self-aggregation rate. Molecular docking indicates that the Aß fibril-binding ligands bind to the D23N and WT forms at different poses. These compounds prefer to bind to the N-terminal ß-strand of the D23N mutant trimer, while they mostly bind to the N-terminal loop region of the WT. It is important to take into account the difference in the binding of ligands to mutant and wild type Aß peptides in designing efficient inhibitors for various types of AD.