Mechanistic insights into the mitigation of Aβ aggregation and protofibril destabilization by ad-enantiomeric decapeptide rk10

Physical Chemistry Chemical Physics, Journal Year: 2022, Volume and Issue: 24(36), P. 21975 - 21994

Published: Jan. 1, 2022

According to clinical studies, the development of Alzheimer's disease (AD) is linked abnormal aggregation amyloid-β (Aβ) peptides into toxic soluble oligomers, protofibrils as well mature fibrils. The most acceptable therapeutic strategy for treatment AD block Aβ aggregation. Sun and co-workers have reported a decapeptide, D-enantiomeric RTHLVFFARK-NH2 (rk10), which acts potent inhibitor efficiently disaggregates pre-assembled However, inhibitory mechanism rk10 against disassembly fibrils remains obscure. To investigate fibrils, molecular dynamics (MD) simulations been performed in present study. docking analysis using AutoDock Vina predicted favourable binding with N-terminal central hydrophobic core (CHC) residues Aβ42 monomer (-5.3 kcal mol-1), chain A protofibril structure (-6.9 mol-1). MD depicted higher structural stability presence rk10. Notably, prevented sampling β-sheet rich structures by reducing side-chain contacts between C-terminal monomer. per-residue free energy highlighted significant contribution Phe19 Glu22 rk10, corroborate 1H NMR (nuclear magnetic resonance) spectra + complex that change chemical shifts amide protons Glu22. Further, destabilized lowering number interchain hydrogen bonds. lower affinity chains compared alone. insights will be beneficial design anti-amyloid inhibitors.

Language: Английский

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The Molecular Mechanism of PSMα3 Aggregation: A New View

The Journal of Physical Chemistry B, Journal Year: 2023, Volume and Issue: 127(39), P. 8317 - 8330

Published: Sept. 21, 2023

The emergence of a novel cross-α fibrillar structure, unlike the commonly observed sequence-independent cross-β one, 22-residue bacterial virulent amphipathic α-helical peptide phenol soluble modulin (PSM) family, PSMα3, with many deleterious effects on human life, has infused uncertainty to paradigm intrinsically polymorphic, multivariate, multiphasic, and cross-sequence–cross-disease entangled protein aggregation landscape hence identity therapeutic target. We, here, deconvolute factors contributing genesis transition lower higher order aggregates PSMα3 in its natural state three noncanonical designed variants using conventional enhanced sampling approach-based atomistic simulations. shows structural polymorphism nominal α-helicity, substantial β-propensity, dominant random-coil features, irrespective extent aggregation. Moreover, individual features overall amphipathicity operate alternatively depending organization aggregation; dominance gradually moves from charged hydrophobic residues progressive generation (dimer oligomer fibril) increasing orderedness self-assembled construct (oligomer vs dimer/fibril). Similarly, contribution interchain salt bridges decreases fibril). However, intrachain consistently display their role all phases Such phase-independent also include equivalent roles electrostatic van der Waals forces interactions, sole cross-talk, negligible peptide–water relationship. Finally, we propose conjugate peptide-based suppressor having single-point proline mutation.

Language: Английский

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Structural Reorganization Mechanism of the Aβ₄₂ Fibril Mediated by N-Substituted Oligopyrrolamide ADH-353

ACS Chemical Neuroscience, Journal Year: 2024, Volume and Issue: 15(17), P. 3136 - 3151

Published: Aug. 19, 2024

The inhibition of amyloid-β (Aβ) fibrillation and clearance Aβ aggregates have emerged as a potential pharmacological strategy to alleviate aggregate-induced neurotoxicity in Alzheimer's disease (AD). Maity et al. shortlisted ADH-353 from small library positively charged N-substituted oligopyrrolamides for its notable ability inhibit fibrillation, disintegrate intracellular cytotoxic oligomers, Aβ-induced cytotoxicity the SH-SY5Y N2a cells. However, molecular mechanism through which interacts with Aβ42 fibrils, leading their disruption subsequent clearance, remains unclear. Thus, detailed underlying neurotoxic fibrils (PDB ID 2NAO) by has been illuminated this work using dynamics simulations. Interestingly, conformational snapshots during simulation depicted shortening disappearance β-strands emergence helix conformation, indicating loss well-organized β-sheet-rich structure disease-relevant fibril on incorporation ADH-353. binds strongly (ΔGbinding= −142.91 ± 1.61 kcal/mol) contribution electrostatic interactions between N-propylamine side chains glutamic (Glu3, Glu11, Glu22) aspartic (Asp7 Asp23) acid residues fibril. This aligns well heteronuclear single quantum coherence NMR studies, depict that binding peptide is driven hydrophobic contacts. Furthermore, noteworthy decrease affinity indicates weakening interchain double-horseshoe conformation illumination key responsible destabilization will greatly aid designing new chemical scaffolds enhanced efficacy AD.

Language: Английский

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Insights into the baicalein-induced destabilization of LS-shaped Aβ₄₂ protofibril using computer simulations

Physical Chemistry Chemical Physics, Journal Year: 2024, Volume and Issue: 26(23), P. 16674 - 16686

Published: Jan. 1, 2024

MD simulations illuminated the molecular mechanism of baicalein-induced destabilization LS-shaped Aβ 42 protofibrils. Baicalein destabilizes protofibrils by lowering β-sheets, elongating kink angle, and disrupting K28–A42 salt bridges.

Language: Английский

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Unveiling molecular mechanism underlying inhibition of human islet amyloid polypeptide fibrillation by benzene carboxylic acid-peptide conjugate

Journal of Molecular Liquids, Journal Year: 2024, Volume and Issue: 416, P. 126426 - 126426

Published: Nov. 7, 2024

Language: Английский

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