Background: The molecular tweezer, CLR01, binds to Lys and prevents aggregation of ␣-synuclein. Results: CLR01 binds directly to monomeric ␣-synuclein near the N terminus and changes the charge distribution in the sequence, swelling the chain, and increasing the protein reconfiguration rate. Conclusion: Aggregation is inhibited by making the protein more diffusive. Significance: The most effective aggregation inhibitors may change monomer dynamics rather than structure.
The self-propagation of misfolded conformations of tau underlies neurodegenerative diseases, including Alzheimer’s disease. There is considerable interest in discovering the minimal sequence and active conformational nucleus that defines this self-propagating event. The microtubule-binding region, spanning residues 244-372, reproduces much of the aggregation behavior of tau in cells and animal models. Further dissection of the amyloid-forming region to a hexapeptide from the third microtubule-binding repeat resulted in a peptide that rapidly forms fibrils in vitro. We show here that this peptide lacks the ability to seed aggregation of tau244-372 in cells. However, as the hexapeptide is gradually extended to 31 residues, the peptides aggregate more slowly and gain potent activity to induce aggregation of tau244-372 in cells. X-ray fiber diffraction, hydrogen-deuterium exchange and solids NMR studies map the beta-forming region to a 25-residue sequence. Thus, the nucleus for self-propagating aggregation of tau244-372 in cells is packaged in a remarkably small peptide.
The B1 domain of protein G has been a classic model system of folding for decades, the subject of numerous experimental and computational studies. Most of the experimental work has focused on whether the protein folds via an intermediate, but the evidence is mostly limited to relatively slow kinetic observations with a few structural probes. In this work we observe folding on the submillisecond timescale with microfluidic mixers using a variety of probes including tryptophan fluorescence, circular dichroism, and photochemical oxidation. We find that each probe yields different kinetics and compare these observations with a Markov State Model constructed from large-scale molecular dynamics simulations and find a complex network of states that yield different kinetics for different observables. We conclude that there are many folding pathways before the final folding step and that these paths do not have large free energy barriers.
lipid bilayer interactions. To understand Ab-lipid interactions at molecular level, we have performed all-atom explicit solvent replica exchange molecular dynamics simulations in the isobaric-isothermal ensemble of the Ab monomer binding to the zwitterionic DMPC bilayer. Upon binding, Ab undergoes a dramatic structural transition from random coil state in water to a state predominated by stable helical structure in the peptide's hydrophobic C-terminal and, to a lesser extent, the central hydrophobic cluster. In addition, binding to the lipid bilayer induces the formation of the intrapeptide Asp23-Lys28 salt bridge. The peptide's C-terminal and central hydrophobic cluster do not only govern binding to the bilayer but they also penetrate into the bilayer core. In contrast, the polar N-terminal and turn region remain solvated and mainly form interactions with the bilayer surface. This partial insertion of Ab reduces the local density of lipids and creates an indentation in the bilayer. Surprisingly, peptide insertion does not significantly distort lipid structural properties or enhance water permeation. Taken together, these results suggest that Ab aggregation in the presence of a zwitterionic lipid bilayer is likely to be different from that in bulk water. Small structural perturbations in lipids induced by the Ab monomer may constitute the molecular basis of its low cytotoxicity.
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