Takako Takeda

Interpeptide interactions induce helix to strand structural transition in Aβ peptides

Replica exchange molecular dynamics and all‐atom implicit solvent model are used to compute the structural propensities in Aβ monomers, dimers, and Aβ peptides bound to the edge of amyloid fibril. These systems represent, on an approximate level, different stages in Aβ aggregation. Aβ monomers are shown to form helical structure in the N‐terminal (residues 13 to 21). Interpeptide interactions in Aβ dimers and, especially, in the peptides bound to the fibril induce a dramatic shift in the secondary structure, from helical states toward β‐strand conformations. The sequence region 10–23 in Aβ peptide is found to form most of interpeptide interactions upon aggregation. Simulation results are tested by comparing the chemical shifts in Aβ monomers computed from simulations and obtained experimentally. Possible implications of our simulations for designing aggregation‐resistant variants of Aβ are discussed. Proteins 2009.

Replica Exchange Simulations of the Thermodynamics of Aβ Fibril Growth

Replica exchange molecular dynamics and an all-atom implicit solvent model are used to probe the thermodynamics of deposition of Alzheimers Abeta monomers on preformed amyloid fibrils. Consistent with the experiments, two deposition stages have been identified. The docking stage occurs over a wide temperature range, starting with the formation of the first peptide-fibril interactions at 500 K. Docking is completed when a peptide fully adsorbs on the fibril edge at the temperature of 380 K. The docking transition appears to be continuous, and occurs without free energy barriers or intermediates. During docking, incoming Abeta monomer adopts a disordered structure on the fibril edge. The locking stage occurs at the temperature of approximately 360 K and is characterized by the rugged free energy landscape. Locking takes place when incoming Abeta peptide forms a parallel beta-sheet structure on the fibril edge. Because the beta-sheets formed by locked Abeta peptides are typically off-registry, the structure of the locked phase differs from the structure of the fibril interior. The study also reports that binding affinities of two distinct fibril edges with respect to incoming Abeta peptides are different. The peptides bound to the concave edge have significantly lower free energy compared to those bound on the convex edge. Comparison with the available experimental data is discussed.

Molecular Dynamics Simulations of Ibuprofen Binding to Aβ Peptides

Using replica exchange molecular dynamics simulations and the implicit solvent model we probed binding of ibuprofen to Abeta(10-40) monomers and amyloid fibrils. We found that the concave (CV) fibril edge has significantly higher binding affinity for ibuprofen than the convex edge. Furthermore, binding of ibuprofen to Abeta monomers, as compared to fibrils, results in a smaller free energy gain. The difference in binding free energies is likely to be related to the presence of the groove on the CV fibril edge, in which ibuprofen tends to accumulate. The confinement effect of the groove promotes the formation of large low-energy ibuprofen clusters, which rarely occur on the surface of Abeta monomers. These observations led us to suggest that the ibuprofen binding mechanism for Abeta fibrils is different from that for monomers. In general, ibuprofen shows a preference to bind to those regions of Abeta monomers (amino terminal) and fibrils (the CV edge) that are also the primary aggregation interfaces. Based on our findings and on available experimental data, we propose a rationale for the ibuprofen antiaggregation effect.

Mapping conformational ensembles of aβ oligomers in molecular dynamics simulations.

Although the oligomers formed by Aβ peptides appear to be the primary cytotoxic species in Alzheimers 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.

Probing the effect of amino-terminal truncation for Abeta1-40 peptides.

We examine the effect of deletion of the amino-terminal (residues 1-9) on the structure and energetics of Abeta1-40 peptides. To this end, we use replica exchange molecular dynamics to compare the conformational ensembles of Abeta1-40 and amino-truncated Abeta10-40 monomers and dimers. Overall, the deletion of the amino-terminal appears to cause minor structural and energetic changes in Abeta monomers and dimers. More specifically, our findings are as follows: (1) there is a small but discernible conversion of beta-strand structure into helix upon amino-terminal deletion, (2) secondary structure changes due to truncation are caused by missing side chain interactions formed by the amino-terminal, and (3) the amino-terminal together with the central sequence region (residues 10-23) represents the primary aggregation interface in Abeta1-40 dimers. The amino-truncated Abeta10-40 retains this aggregation interface, which is reduced to the central sequence region. We argue that the analysis of available experimental data supports our conclusions. Our findings also suggest that amino-truncated Abeta10-40 peptide is an adequate model for studying Abeta1-40 aggregation.

Probing Energetics of Aβ Fibril Elongation by Molecular Dynamics Simulations

Using replica exchange molecular dynamics simulations and an all-atom implicit solvent model, we probed the energetics of Abeta(10-40) fibril growth. The analysis of the interactions between incoming Abeta peptides and the fibril led us to two conclusions. First, considerable variations in fibril binding propensities are observed along the Abeta sequence. The peptides in the fibril and those binding to its edge interact primarily through their N-termini. Therefore, the mutations affecting the Abeta positions 10-23 are expected to have the largest impact on fibril elongation compared with those occurring in the C-terminus and turn. Second, we performed weak perturbations of the binding free energy landscape by scanning partial deletions of side-chain interactions at various Abeta sequence positions. The results imply that strong side-chain interactions--in particular, hydrophobic contacts--impede fibril growth by favoring disordered docking of incoming peptides. Therefore, fibril elongation may be promoted by moderate reduction of Abeta hydrophobicity. The comparison with available experimental data is presented.

Binding of nonsteroidal anti‐inflammatory drugs to Aβ fibril

Nonsteroidal anti‐inflammatory drugs are considered as potential therapeutic agents against Alzheimers disease. Using replica exchange molecular dynamics and atomistic implicit solvent model, we studied the mechanisms of binding of naproxen and ibuprofen to the Aβ fibril derived from solid‐state NMR measurements. The binding temperature of naproxen is found to be almost 40 K higher than of ibuprofen implicating higher binding affinity of naproxen. The key factor, which enhances naproxen binding, is strong interactions between ligands bound to the surface of the fibril. The naphthalene ring in naproxen appears to provide a dominant contribution to ligand‐ligand interactions. In contrast, ligand‐fibril interactions cannot explain differences in the binding affinities of naproxen and ibuprofen. The concave fibril edge with the groove is identified as the primary binding location for both ligands. We show that confinement of the ligands to the groove facilitates ligand‐ligand interactions that lowers the energy of the ligands bound to the concave edge compared with those bound to the convex edge. Our simulations appear to provide microscopic rationale for the differing binding affinities of naproxen and ibuprofen observed experimentally. Proteins 2010.

Nonsteroidal anti-inflammatory drug naproxen destabilizes Aβ amyloid fibrils: a molecular dynamics investigation.

Using implicit solvent model and replica exchange molecular dynamics, we examine the propensity of a nonsteroidal anti-inflammatory drug, naproxen, to interfere with Aβ fibril growth. We also compare the antiaggregation propensity of naproxen with that of ibuprofen. Naproxens antiaggregation effect is influenced by two factors. Similar to ibuprofen, naproxen destabilizes binding of incoming Aβ peptides to the fibril due to direct competition between the ligands and the peptides for the same binding location on the fibril surface (the edge). However, in contrast to ibuprofen, naproxen binding also alters the conformational ensemble of Aβ monomers by promoting β-structure. The second factor weakens naproxens antiaggregation effect. These findings appear to explain the experimental observations, in which naproxen binds to the Aβ fibril with higher affinity than ibuprofen, yet produces weaker antiaggregation action.

Molecular Dynamics Simulations of Anti-Aggregation Effect of Ibuprofen

Using implicit solvent molecular dynamics and replica exchange simulations, we study the impact of ibuprofen on the growth of wild-type Abeta fibrils. We show that binding of ibuprofen to Abeta destabilizes the interactions between incoming peptides and the fibril. As a result, ibuprofen interference modifies the free energy landscape of fibril growth and reduces the free energy gain of Abeta peptide binding to the fibril by approximately 2.5 RT at 360 K. Furthermore, ibuprofen interactions shift the thermodynamic equilibrium from fibril-like locked states to disordered docked states. Ibuprofens anti-aggregation effect is explained by its competition with incoming Abeta peptides for the same binding site located on the fibril edge. Although ibuprofen impedes fibril growth, it does not significantly change the mechanism of fibril elongation or the structure of Abeta peptides bound to the fibril.

Temperature-Induced Dissociation of Aβ Monomers from Amyloid Fibril

Using all-atom molecular dynamics, we study the temperature-induced dissociation of Abeta monomers from the fibril protofilament. To accelerate conformational sampling, simulations are performed at elevated temperatures and peptide concentrations. By computing free energy disconnectivity graphs we mapped the free energy landscape of monomers on the surface of Abeta fibril. We found that Abeta monomers sample diverse sets of low free energy states with different degrees of association with the fibril. Some of these states have residual amounts of fibril interactions, whereas others lack fibril-like content. Generally, Abeta monomers with partially formed fibril-like interactions have the lowest free energies, but their backbone conformations may differ considerably from those in the fibril interior. Overall, Abeta amyloid protofilaments seem to be highly resistant to thermal dissociation. Monomer dissociation from the fibril edge proceeds via multiple stages and pathways. Our simulation findings are discussed in the context of recent experimental results.