Aggregating the amyloid Aβ11-25 peptide into a four-stranded β-sheet structure (original) (raw)
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Aggregating the amyloid Abeta(11-25) peptide into a four-stranded beta-sheet structure
Proteins, 2006
We present a detailed analysis of the structural properties of one monomer of Abeta(11-25) as well as of the aggregation mechanisms for four chains of Abeta(11-25) using the activation-relaxation technique coupled with a generic energy potential. Starting from a random distribution of these four chains, we find that the system assembles rapidly into a random globular state that evolves into three- and four-stranded antiparallel beta-sheets. The aggregation process is considerably accelerated by the presence of preformed dimers. We also find that the reptation mechanism already identified in shorter peptides plays a significant role here in allowing the structure to reorganize without having to fully dissociate.
Journal of Molecular Biology, 2005
Characterization of the early stages of peptide aggregation is of fundamental importance in elucidating the mechanism of the formation of deposits associated with amyloid disease. The initial step in the pathway of aggregation of the Ab-protein, whose monomeric NMR structure is known, was studied through the simulation of the structure and stability of the peptide dimer in aqueous solution. A protocol based on shape complementarity was used to generate an assortment of possible dimer structures. The structures generated based on shape complementarity were evaluated using rapidly computed estimates of the desolvation and electrostatic interaction energies to identify a putative stable dimer structure. The potential of mean force associated with the dimerization of the peptides in aqueous solution was computed for both the hydrophobic and the electrostatic driven forces using umbrella sampling and classical molecular dynamics simulation at constant temperature and pressure with explicit solvent and periodic boundary conditions. The comparison of the two free energy profiles suggests that the structure of the peptide dimer is determined by the favorable desolvation of the hydrophobic residues at the interface. Molecular dynamics trajectories originating from two putative dimer structures indicate that the peptide dimer is stabilized primarily through hydrophobic interactions, while the conformations of the peptide monomers undergo substantial structural reorganization in the dimerization process. The finding that the 4-dimer may constitute the ensemble of stable Ab 10-35 dimer has important implications for fibril formation. In particular, the expulsion of water molecules at the interface might be a key event, just as in the oligomerization of Ab 16-22 fragments. We conjecture that events prior to the nucleation process themselves might involve crossing free energy barriers which depend on the peptide-peptide and peptide-water interactions. Consistent with existing experimental studies, the peptides within the ensemble of aggregated states show no signs of formation of secondary structure.
The Journal of Physical Chemistry B, 2011
The β amyloid (Aβ) peptide aggregates to form β-rich structures that are known to trigger Alzheimer's disease. Experiments suggest that an α-helical intermediate precedes the formation of these aggregates. However, a description at the molecular level of the α-to-β transition has not been obtained. Because it has been proposed that the transition might be initiated in the aminoterminal region of Aβ, we studied the aggregation of the 28-residue amino-terminal fragment of Aβ (Aβ 1-28) using molecular dynamics and a coarse-grained force field. Simulations starting from extended and helical conformations showed that oligomerization is initiated by formation of intermolecular β-sheets between the residues in the N-terminal regions. In simulations starting from the α-helical conformation, forcing residues 17-21 to remain in the initial (helical) conformation prevents aggregation but allows for the formation of dimers, indicating that oligomerization, initiated along the non-helical N-terminal regions, cannot progress without the αto-β transition propagating along the chains.
ACS Chemical Neuroscience, 2010
Neuronal cytotoxicity observed in Alzheimer's disease (AD) is linked to the aggregation of β-amyloid peptide (Aβ) into toxic forms. Increasing evidence points to oligomeric materials as the neurotoxic species, not Aβ fibrils; disruption or inhibition of Aβ self-assembly into oligomeric or fibrillar forms remains a viable therapeutic strategy to reduce Aβ neurotoxicity. We describe the synthesis and characterization of amyloid aggregation mitigating peptides (AAMPs) whose structure is based on the Aβ "hydrophobic core" Aβ 17-20 , with R,R-disubstituted amino acids (RRAAs) added into this core as potential disrupting agents of fibril selfassembly. The number, positional distribution, and side-chain functionality of RRAAs incorporated into the AAMP sequence were found to influence the resultant aggregate morphology as indicated by ex situ experiments using atomic force microscopy (AFM) and transmission electron microscopy (TEM). For instance, AAMP-5, incorporating a sterically hindered RRAA with a diisobutyl side chain in the core sequence, disrupted Aβ 1-40 fibril formation. However, AAMP-6, with a less sterically hindered RRAA with a dipropyl side chain, altered fibril morphology, producing shorter and larger sized fibrils (compared with those of Aβ 1-40). Remarkably, RRAA-AAMPs caused disassembly of existing Aβ fibrils to produce either spherical aggregates or protofibrillar structures, suggesting the existence of equilibrium between fibrils and prefibrillar structures.
Amyloid-β peptide structure in aqueous solution varies with fragment size
The Journal of chemical physics, 2011
Phase diagram of polypeptide chains JCP: BioChem. Phys. 5, 11B602 (2011) Effects of surface interactions on peptide aggregate morphology JCP: BioChem. Phys. 5, 08B624 (2011) Effects of surface interactions on peptide aggregate morphology J. Chem. Phys. 135, 085102 (2011) Does amino acid sequence determine the properties of A dimer? J. Chem. Phys. 135, 035103 (2011) Additional information on J. Chem. Phys.
Amyloid Formation from an α-Helix Peptide Bundle Is Seeded by 310-Helix Aggregates
Chemistry - A European Journal, 2011
mediate satisfies the need for peptide elongation, from the compressed a helix to the fully extended b strand/ sheet, and is driven here by 3 10 -helix aggregation triggered in this case by template-promoted helical bundling and by hydrogen-bonding glutamic acid side chains. A mechanism involving a)À * a 4 )À * (3 10 ) 4 Ð(3 10 ) n )À * (b) n À+ ( m(b) n equilibria is plausible for this peptide and also for peptides lacking hydrogenbonding side chains, with unfavourable equilibria slowing the a!b conversion.
2000
Substantial clinical and experimental evidence supports the hypothesis that amyloid β-protein (Aβ) forms assemblies with potent neurotoxic properties that cause Alzheimer's disease (AD). Therapeutic targeting of these assemblies would be facilitated by the elucidation of the structural dynamics of Aβ aggregation at atomic resolution. We apply the ab initio discrete molecular dynamics approach coupled with a four-bead peptide model to study the aggregation of wild-type and Arctic-mutant (E22G) Aβ 16−22 , a peptide that contains the Aβ central hydrophobic cluster, Leu 17 -Ala 21 , that plays an important role in Aβ assembly. The aggregation of sixteen wild-type Aβ 16−22 peptides is studied systematically under solvent conditions incorporating: (i) effective hydropathic and electrostatic interactions; (ii) no effective hydropathic interactions; and (iii) no effective electrostatic interactions. We find that at physiological temperatures initially-separated peptides aggregate into fibrillar units under condition (i). These units comprise multi-layered β-sheets with cross-β structure and an antiparallel arrangement of β-strands. Under condition (iii), β-strands are arranged either in a parallel or antiparallel manner, suggesting that electrostatic interactions control β-sheet organization. For condition (ii), no fully-formed fibrillar aggregates are observed, only occasional antiparallel β-strands. Fibrillar aggregates of Arctic-mutant Aβ 16−22 peptides have parallel as well as antiparallel β-strands resembling the aggregates of wild-type Aβ 16−22 peptides with no electrostatic interaction. We find that flexibility of peptide backbone is an important factor required for fibrillization. Arctic-mutant Aβ 16−22 peptides oligomerize slower due to negligible role of electrostatic interaction in driving oligomerization, but fibrillize faster due to greater flexibility and ease of rearrangement with smaller volume and no charge of G22 than wild-type. It implies that electrostatic interaction cooperatively drives initial oligomerization of Aβ with hydropathic interaction.