Alzheimer’s disease (AD) is a progressive neurodegenerative disease with no clinically accepted treatment to cure or halt its progression. The worldwide effort to develop peptide-based inhibitors of amyloid-β (Aβ) aggregation can be considered an unplanned combinatorial experiment. An understanding of what has been done and achieved may advance our understanding of AD pathology and the discovery of effective therapeutic agents. We review here the history of such peptide-based inhibitors, including those based on the Aβ sequence and those not derived from that sequence, containing both natural and unnatural amino acid building blocks. Peptide-based aggregation inhibitors hold significant promise for future AD therapy owing to their high selectivity, effectiveness, low toxicity, good tolerance, low accumulation in tissues, high chemical and biological diversity, possibility of rational design, and highly developed methods for analyzing their mode of action, proteolytic stability (modified peptides), and blo...

Rationally Designed Peptides and Peptidomimetics as Inhibitors of Amyloid-β (Aβ) Aggregation: Potential Therapeutics of Alzheimer’s Disease

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized by loss of intellectual functioning of brain and memory loss. According to amyloid cascade hypothesis, aggregation of amyloid-β42 (Aβ42) peptide can generate toxic oligomers and their accumulation in the brain is responsible for the onset of AD. In spite of carrying out a large number of experimental studies on inhibition of Aβ42 aggregation by small molecules, the detailed inhibitory mechanism remains elusive. In the present study, comparable molecular dynamics (MD) simulations were performed to elucidate the inhibitory mechanism of a sulfonamide inhibitor C1 (2,5-dichloro-N-(4-piperidinophenyl)-3-thiophenesulfonamide), reported for its in vitro and in vivo anti-aggregation activity against Aβ42. MD simulations reveal that C1 stabilizes native α-helix conformation of Aβ42 by interacting with key residues in the central helix region (13-26) with hydrogen bonds and π-π interactions. C1 lowers the solvent-accessible surface area of the central hydrophobic core (CHC), KLVFF (16-20), that confirms burial of hydrophobic residues leading to the dominance of helical conformation in the CHC region. The binding free energy analysis with MM-PBSA demonstrates that Ala2, Phe4, Tyr10, Gln15, Lys16, Leu17, Val18, Phe19, Phe20, Glu22, and Met35 contribute maximum to binding free energy (-43.1 kcal/mol) between C1 and Aβ42 monomer. Overall, MD simulations reveal that C1 inhibits Aβ42 aggregation by stabilizing native helical conformation and inhibiting the formation of aggregation-prone β-sheet conformation. The present results will shed light on the underlying inhibitory mechanism of small molecules that show potential in vitro anti-aggregation activity against Aβ42.

Scrutiny of the mechanism of small molecule inhibitor preventing conformational transition of amyloid-β42 monomer: insights from molecular dynamics simulations.

Insights into the Inhibitory Mechanism of Dicyanovinyl‐Substituted J147 Derivative against Aβ42 Aggregation and Protofibril Destabilization: A Molecular Dynamics Simulation Study

The aggregation of amyloid β-peptide (Aβ42) into toxic oligomers, fibrils, has been identified as a key process in Alzheimer's disease (AD) progression. The role of halogen-substituted compounds have been highlighted in the disassembly of Aβ protofibril. However, the underlying inhibitory mechanism of Aβ42 protofibril destabilization remains elusive. In this regard, a combined molecular docking and molecular dynamics (MD) simulations were performed to elucidate the inhibitory mechanism of a fluorinated compound, D744, which has been reported previously for potential in vitro and in vivo inhibitory activity against Aβ42 aggregation and reduction in the Aβ-induced cytotoxicity. The molecular docking analysis highlights that D744 binds and interacts with chain A of the protofibril structure with hydrophobic contacts and orthogonal multipolar interaction. MD simulations reveal destabilization of the protofibril structure in the presence of D744 due to the decrease in β-sheet content and a concomitant increase of coil and bend structures, increase in the interchain D23-K28 salt bridge distance, decrease in the number of backbone hydrogen bonds, increase in the average distance between Cα atoms, and decrease in the binding affinity between chains A and B of the protofibril structure. The binding free-energy analysis between D744 and the protofibril structure with Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) reveal that residues Leu17, Val18, Phe19, Phe20, Ala21, Glu22, Asp23, Leu34, Val36, Gly37, and Gly38 of chain A of the protofibril structure contribute maximum towards binding free energy (ΔGbinding = −44.87 kcal/mol). The insights into the underlying inhibitory mechanism of small molecules that show potential in vitro anti-aggregation activity against Aβ42 will be beneficial for the current and future AD therapeutic studies.

Molecular insights into Aβ42 protofibril destabilization with a fluorinated compound D744: A molecular dynamics simulation study.

A fundamental and still debated problem is how folded structures of proteins are related to their unfolded state. Besides the classical view, in which a large number of conformations characterize the unfolded state while the folded one is dominated by a single structure, recently a reassessment of the denatured state has been suggested. A growing amount of evidence indicates that not only the folded but also the unfolded state is at least partially organized. Here, we try to answer the question of how different protein dynamics is in folded and unfolded states by performing all-atom molecular dynamics simulations on the model protein Trp-cage. Random matrix theory inspired analysis of the correlation matrices has been carried out. The spectra of these correlation matrices show that the low rank modes of Trp-cage dynamics are outside of the limit expected for a random system both in folded and in unfolded conditions. These findings shed light on the nature of the unfolded state of the proteins, suggesting ...

Correlation Analysis of Trp-Cage Dynamics in Folded and Unfolded States.

A fundamental open problem in biophysics is how the folded structure of the main chain (MC) of a protein is determined by the physics of the interactions between the side chains (SCs). All-atom molecular dynamics simulations of a model protein (Trp-cage) revealed that strong correlations between the motions of the SCs and the MC occur transiently at 380 K in unfolded segments of the protein and during the simulations of the whole amino-acid sequence at 450 K. The high correlation between the SC and MC fluctuations is a fundamental property of the unfolded state and is also relevant to unstructured proteins as intrinsically disordered proteins (IDPs), for which new reaction coordinates are introduced. The presented findings may open a new door as to how functions of IDPs are related to conformations, which play a crucial role in neurodegenerative diseases.

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New Insights into Protein (Un)Folding Dynamics.

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New Insights into Protein (Un)Folding Dynamics.