Globular state in the oligomers formed by Aβ peptides

Self Cite

Experimental and epidemiological studies have shown that the nonsteroidal antiinflammatory drug naproxen may be useful in the treatment of Alzheimer's disease. To investigate the interactions of naproxen with Aβ dimers, which are the smallest cytotoxic aggregated Aβ peptide species, we use united atom implicit solvent model and exhaustive replica exchange molecular dynamics. We show that naproxen ligands bind to Aβ dimer and penetrate its volume interfering with the interpeptide interactions. As a result naproxen induces a destabilizing effect on Aβ dimer. By comparing the free-energy landscapes of naproxen interactions with Aβ dimers and fibrils, we conclude that this ligand has stronger antiaggregation potential against Aβ fibrils rather than against dimers. The analysis of naproxen binding energetics shows that the location of ligand binding sites in Aβ dimer is dictated by the Aβ amino acid sequence. Comparison of the in silico findings with experimental observations reveals potential limitations of naproxen as an effective therapeutic agent in the treatment of Alzheimer's disease.

Section: Naproxen Destabilizes Ab Dimermentioning

confidence: 73%

“…To study the changes in the dimer size, the inset to Fig. 3 a displays the temperature dependences of the core volumes computed for naproxen solution and water (49), V c ðTÞ and V c ðT; wÞ, respectively. At T(400 K, the Ab dimer coincubated with naproxen expands compared to the ligand-free environment.…”

Section: Naproxen Destabilizes Ab Dimermentioning

confidence: 99%

Naproxen Interferes with the Assembly of Aβ Oligomers Implicated in Alzheimer's Disease

Kim

Chang

Kumar

et al. 2011

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“…The distributions of states produced by REMD were analyzed using multiple histogram method (46). The convergence of REMD simulations and error analysis were reported in our previous studies (28,43). In particular, the thermodynamic quantities probing inter-and intrapeptide interactions have the errors of 1% (tetramer) and ( 4% (dimer or monomer).…”

Section: Computation Of Structural Probesmentioning

confidence: 99%

“…1). Their description can be found in our previous studies (28,34,43). Briefly, the monomer, dimer, and tetramer systems involve one, two, or four identical unconstrained Ab 10-40 peptides, respectively.…”

Section: Simulation Modelmentioning

confidence: 99%

Mapping Conformational Ensembles of Aβ Oligomers in Molecular Dynamics Simulations

Kim

Takeda

Klimov

2010

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Although the oligomers formed by Aβ peptides appear to be the primary cytotoxic species in Alzheimer's disease, detailed information about their structures appears to be lacking. In this article, we use exhaustive replica exchange molecular dynamics and an implicit solvent united-atom model to study the structural properties of Aβ monomers, dimers, and tetramers. Our analysis suggests that the conformational ensembles of Aβ dimers and tetramers are very similar, but sharply distinct from those sampled by the monomers. The key conformational difference between monomers and oligomers is the formation of β-structure in the oligomers occurring together with the loss of intrapeptide interactions and helix structure. Our simulations indicate that, independent of oligomer order, the Aβ aggregation interface is largely confined to the sequence region 10-23, which forms the bulk of interpeptide interactions. We show that the fractions of β structure computed in our simulations and measured experimentally are in good agreement.

“…Eight figures and references (57)(58)(59) are available at http://www.biophysj. org/biophysj/supplemental/S0006-3495(12)01106-X.…”

Section: Supporting Materialsmentioning

confidence: 99%

Molecular Interactions of Alzheimer's Biomarker FDDNP with Aβ Peptide

Lockhart

Klimov

2012

All-atom explicit solvent model and replica exchange molecular dynamics were used to investigate binding of Alzheimer's biomarker FDDNP to the Aβ(10-40) monomer. At low and high concentrations, FDDNP binds with high affinity to two sites in the Aβ(10-40) monomer located near the central hydrophobic cluster and in the C-terminal. Analysis of ligand- Aβ(10-40) interactions at both concentrations identifies hydrophobic effect as a main binding factor. However, with the increase in ligand concentration the interactions between FDDNP molecules also become important due to strong FDDNP self-aggregation propensity and few specific binding locations. As a result, FDDNP ligands partially penetrate the core of the Aβ(10-40) monomer, forming large self-aggregated clusters. Ligand self-aggregation does not affect hydrophobic interactions as a main binding factor or the location of binding sites in Aβ(10-40). Using the Aβ(10-40) conformational ensemble in ligand-free water as reference, we show that FDDNP induces minor changes in the Aβ(10-40) secondary structure at two ligand concentrations studied. At the same time, FDDNP significantly alters the peptide tertiary fold in a concentration-dependent manner by redistributing long-range, side-chain interactions. We argue that because FDDNP does not change Aβ(10-40) secondary structure, its antiaggregation effect is likely to be weak. Our study raises the possibility that FDDNP may serve as a biomarker of not only Aβ fibril species, but of monomers as well.