L'Auto-vélo : automobilisme, cyclisme, athlétisme, yachting, aérostation, escrime, hippisme / dir. Henri Desgranges

29 mai 19041904/05/29 (A5,N1325)

Amphiphilic Peptides A₆K and V₆K Display Distinct Oligomeric Structures and Self-Assembly Dynamics: A Combined All-Atom and Coarse-Grained Simulation Study

Amphiphilic peptides can self-assemble into ordered nanostructures with different morphologies. However, the assembly mechanism and the structures of the early assemblies prior to nanostructure formation remain elusive. In this study, we investigated the oligomeric structures of two amphiphilic heptapeptides A₆K and V₆K by all-atom explicit-solvent replica-exchange molecular dynamics (REMD) simulations, and then examined the assembly dynamics of large aggregates by coarse-grained (CG) MD simulations. Our 200 ns REMD simulations show that A₆K peptides predominantly adopt loosely packed disordered coil aggregates, whereas V₆K peptides mostly assemble into compact β-sheet-rich conformations, consistent with the signal measured experimentally in aqueous solution. Well-organized β-sheet-rich conformations, albeit with low population, are also populated for V₆K octamers, including bilayer β-sheets and β-barrels. These ordered β-sheet-rich conformations are observed for the first time for amphiphilic peptides. Our 10-μs CG-MD simulations on 200 peptide chains demonstrate that A₆K and V₆K peptides follow two different self-assembly processes, and the former form monolayer lamellas while the latter assemble into plate-like assemblies. CG-MD simulations also show that V₆K peptides display higher assembly capability than A₆K, in support of our all-atom REMD simulation results. Interpeptide interaction analyses reveal that the marked differences in oligomeric structures and assembly dynamics between A₆K and V₆K result from the subtle interplay of competition among hydrophobic, hydrogen-bonding, and electrostatic interactions of the two peptides. Our study provides structural and mechanistic insights into the initial self-assembly process of A₆K and V₆K at the molecular level

Orcein-Related Small Molecule O4 Destabilizes hIAPP Protofibrils by Interacting Mostly with the Amyloidogenic Core Region

The accumulation of the human islet amyloid polypeptide (hIAPP) deposits in the pancreas is regarded as an important factor that leads to the depletion of islet β-cells and islet transplantation failure. In recent experiments, it was reported that a small organic molecule O4 inhibits the formation of hIAPP1-37 oligomers and fibrils. However, the interaction between O4 molecules and hIAPP oligomers is largely unknown on the atomic level. In this work, we studied the influence of O4 molecules on fibril-like hIAPP pentamer and decamer by performing atomistic molecular dynamics simulations. Our results show that O4 molecules mostly bind to the amyloid core region spanning residues 22NFGAI26 for both hIAPP pentamer and decamer, which leads to the local disruption of interpeptide β-sheets. The calculation of contact probability and binding energy indicates that the binding of O4 molecules is mostly driven by aromatic stacking and hydrophobic interactions. Our work reveals the detailed disruption mechanism of full-length hIAPP protofibrils by O4 molecules and may be helpful to the design of more efficient inhibitors against hIAPP aggregation