In this simulation study, we present a comparison of the secondary structure of the two major alloforms of the Alzheimer's peptide (Aβ(1-40) and Aβ(1-42)) on the basis of molecular dynamics (MD) simulations on thea microsecond time scale using the two GROMOS96 force fields ffG43a2 and ffG53a6. We observe peptide and force-field related differences in the sampled conformations of Aβ(1-40) and Aβ(1-42), which we characterize in terms of NMR chemical shifts calculated from the MD trajectories and validate against the corresponding experimental NMR results. From this analysis, we can conclude that ffG53a6 is better able to model the structural propensities of Aβ(1-40) and Aβ(1-42) than ffG43a2. Furthermore, we provide a description of the influences of pH and binding of D3, a 12-residue D-enantiomeric peptide with demonstrated antiamyloid effects, on the structure of Aβ(1-42). We demonstrate that, under slightly acidic conditions, protonation of the three histidine residues in Aβ(1-42) promotes the formation of β-sheets via a reduction in electrostatic repulsion between the two terminal regions. Our studies further reveal that the binding between D3 and Aβ(1-42) is driven by electrostatic interactions between negatively charged Aβ(1-42) residues and the five positively charged arginine residues of D3. The binding of D3 was found to induce large conformational changes in the amyloid peptide, with a reduction in β-sheet units being the most significant effect recorded, possibly explaining the observed amyloid-inhibiting properties of the D-peptide.

The aggregation of amyloid-β protein (1-42) is studied at experimental concentrations using all-atom molecular dynamics simulations. We observe a fast aggregation into oligomers without significant changes in the internal structure of individual proteins. The aggregation process is characterized in terms of transition networks.

We use state-of-the-art computer-aided drug design (CADD) techniques to identify prospective inhibitors of the main protease enzyme, 3CLpro of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing COVID-19. From our screening of over one million compounds including approved drugs, investigational drugs, natural products, and organic compounds, and a rescreening protocol incorporating enzyme dynamics via ensemble docking, we have been able to identify a range of prospective 3CLpro inhibitors. Importantly, some of the identified compounds had previously been reported to exhibit inhibitory activities against the 3CLpro enzyme of the closely related SARS-CoV virus. The top-ranking compounds are characterized by the presence of multiple bi- and monocyclic rings, many of them being heterocycles and aromatic, which are flexibly linked allowing the ligands to adapt to the geometry of the 3CLpro substrate site and involve a high amount of functional groups enabling hydrogen bond formation with surrounding amino acid residues, including the catalytic dyad residues H41 and C145. Among the top binding compounds we identified several tyrosine kinase inhibitors, which include a bioflavonoid, the group of natural products that binds best to 3CLpro. Another class of compounds that decently binds to the SARS-CoV-2 main protease are steroid hormones, which thus may be endogenous inhibitors and might provide an explanation for the age-dependent severity of COVID-19. Many of the compounds identified by our work show a considerably stronger binding than found for reference compounds with in vitro demonstrated 3CLpro inhibition and anticoronavirus activity. The compounds determined in this work thus represent a good starting point for the design of inhibitors of SARS-CoV-2 replication.