Destabilization potential of phenolics on Aβ fibrils: mechanistic insights from molecular dynamics simulation

Abstract

The clinical signature of Alzheimer’s disease (AD) is the deposition of aggregated Aβ fibrils that are neurotoxic to the brain. It is the major form of dementia affecting older people...

Destabilization potential of beta sheet breaker peptides on Abeta fibril structure: an insight from molecular dynamics simulation study

“…The major factors that were considered by most of the researchers for evaluating the destabilization potential of the ligands are secondary structure content especially beta and coil content, salt bridge distance between Asp23-Lys28 (especially in U-shaped model), inter-chain hydrogen and hydrophobic interaction. 64,65,[81][82][83][84][85][86][87] In the current work, it was observed that binding of peptides with Abeta protobril has resulted in the loss of beta structure and gain of coil structure. This is in accordance with previous studies showing increase of coil and decrease of beta structures.…”

“…In another study, Barale et al 87 showed that binding of arginine hybrid peptides to Abeta protofibril destabilize it by breaking of important salt bridge between D23–K28. Gupta et al 65 showed the destabilization ellagic acid (REF) using molecular dynamic simulations. They showed that REF leads to the decrease in beta-structure content, disruption of salt bridges and decline in the number of hydrogen bonds.…”

“…The U-shaped model (2BEG) has been part of most of the previously reported molecular simulation studies. [64][65][66][67][68][69][70] Thus, 2BEG model was selected for the study.…”

Inhibition Mechanisms of (−)-Epigallocatechin-3-gallate and Genistein on Amyloid-beta 42 Peptide of Alzheimer’s Disease via Molecular Simulations

“…Figure b displays the results of the solvent accessibility of the Aβ42 peptide surfaces in different simulation systems. The SASA value is very important for the influence of the configuration of a protein in water . It is obvious that the values of SASA have stabilized at about 33.27 ± 1.12 nm/S 2 /N (Aβ42 peptide), 35.16 ± 3.10 nm/S 2 /N (Aβ42 peptide–EGCG), and 34.37 ± 1.50 nm/S 2 /N (Aβ42 peptide–genistein).…”

Recent Developments in Free Energy Calculations for Drug Discovery

“…Thai et al demonstrate how MM-PBSA can rapidly facilitate drug development by first predicting strong multipotent binding of CID 9998128 with Aβ 42 peptide, Aβ 42 fibrils, and β-secretase, then performing in vitro assays confirming that the compound inhibits Aβ fibril formation ( Thai et al, 2018 ). Other works include the development of positron emission tomography/single photon emission computed tomography probes targeting Aβ for imaging ( Kawai et al, 2018 ), rational design of anti-Aβ antibodies ( Greene et al, 2018 ), small molecule inhibitors targeting Aβ fibrils ( Ngo et al, 2019 ; Gupta and Dasmahapatra, 2020 ), β-sheet breaker peptides to interfere with amyloid fibril assembly ( Shuaib et al, 2019 ), and structural modeling of aspartyl protease γ-secretase in complex with Aβ peptides ( Hitzenberger and Zacharias, 2019 ). Further study of neurodegenerative disease involves fragment docking of reversible covalent inhibitors on calpain, a calcium dependent cysteine protease, whose overexpression has been correlated with neurodegenerative disorders ( Zhang H. et al, 2019 ).…”