Impact of Amidation on Aβ_25–35 Aggregation

The Journal of Physical Chemistry B, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 13, 2025

Toxic oligomeric species are suspected in the etiology of Alzheimer's disease. The full-length Aβ42 can be studied by fragment Aβ25-35 as it retains neurotoxicity. According to experimental studies, amidation carboxyl terminal decreases fibrillation activity while retaining its neurotoxic properties. Our molecular dynamics simulation aggregation trimer from two initial structures (fibril and randomized helical structures) their amidated nonamidated forms. Comparing systems, results suggest that antiparallel chains dominant amide group leads parallel chains. In terms secondary structures, a higher helix content with corresponding decrease β-sheet is observed consequence amidation. Despite variation chain-chain contacts still mediated Gly motif (GxxxG) Ile residues both systems. As neurotoxicity does not change upon amidation, our imply clumping peptides sustained greater contributing factor toxicity than quaternary structures.

Language: Английский

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Functionalized pNIPAM-DNA Hydrogel Colorimetric Platform for Visual Detection of Low-Mass Soluble β-Amyloid Oligomers

Analytical Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: May 7, 2025

Low-mass soluble β-amyloid oligomers (LSAβO) are critical Alzheimer's disease (AD) biomarkers with significant diagnostic and therapeutic potential. However, their application in early screening detection is limited by the reliance on complex analytical instruments procedures. To address this, we developed a visual sensing platform for LSAβO using functionalized pNIPAM-DNA hydrogel. Exploiting temperature-responsive nature of pNIPAM, hydrogel selectively incorporates enriches from solution via temperature-induced expansion contraction. binding to aptamers triggers formation G-quadruplex DNAzymes, which catalyze oxidation 3,3',5,5'-tetramethylbenzidine generate visible colorimetric signal. The hydrogel's small pore size further enhances selectivity excluding larger during real sample analysis. This sensor exhibits linear range 0.1-7.5 nM limit 50 pM. Combining enrichment exclusion, this provides cost-effective, highly sensitive, selective, high-throughput approach preliminary detection.

Language: Английский

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Metastable alpha‐rich and beta‐rich conformations of small Aβ42 peptide oligomers

Proteins Structure Function and Bioinformatics, Journal Year: 2023, Volume and Issue: unknown

Published: April 10, 2023

Abstract Probing the structures of amyloid‐β (Aβ) peptides in early steps aggregation is extremely difficult experimentally and computationally. Yet, this knowledge important as small oligomers are most toxic species. Experiments simulations on Aβ42 monomer point to random coil conformations with either transient helical or β‐strand content. Our current conformational description funneled toward amorphous aggregates some β‐sheet content rare high energy states well‐ordered assemblies β‐sheets. In study, we emphasize another view based metastable α‐helix bundle spanning C‐terminal residues, which predicted by machine‐learning AlphaFold2 method supported indirectly low‐resolution experimental data many amyloid polypeptides. This finding has consequences developing novel chemical tools design potential therapies reduce toxicity.

Language: Английский

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Protein aggregation and neurodegenerative disease: Structural outlook for the novel therapeutics

Proteins Structure Function and Bioinformatics, Journal Year: 2023, Volume and Issue: unknown

Published: Aug. 2, 2023

Abstract Before the controversial approval of humanized monoclonal antibody lecanemab, which binds to soluble amyloid‐β protofibrils, all treatments available earlier, for Alzheimer's disease (AD) were symptomatic. The researchers are still struggling find a breakthrough in AD therapeutic medicine, is partially attributable lack understanding structural information associated with intrinsically disordered proteins and amyloids. One major challenges this area research understand diversity under vitro conditions. Therefore, review, we have summarized applications biophysical methods, aimed shed some light on heterogeneity, pathogenicity, structures mechanisms protein aggregates proteinopathies including AD. This review will also rationalize strategies modulating disease‐relevant pathogenic entities by small molecules using biology approaches characterization. We highlighted tools techniques simulate vivo conditions native cytotoxic tau/amyloids assemblies, urge new chemical replicate assemblies similar those conditions, addition designing novel potential drugs.

Language: Английский

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Recent Computational Advances Regarding Amyloid-β and Tau Membrane Interactions in Alzheimer’s Disease

Molecules, Journal Year: 2023, Volume and Issue: 28(20), P. 7080 - 7080

Published: Oct. 13, 2023

The interactions of amyloid proteins with membranes have been subject to many experimental and computational studies, as these contribute in part neurodegenerative diseases. In this review, we report on recent simulations that focused the adsorption insertion modes amyloid-β tau membranes. atomistic-resolution characterization conformational changes upon lipid cell membrane free is interest rationally design drugs targeting transient oligomers Alzheimer’s disease.

Language: Английский

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Interactions between Lipid Vesicle Membranes and Single Amino Acid Fibrils: Probable Origin of Specific Neurological Disorders

Langmuir, Journal Year: 2024, Volume and Issue: 40(4), P. 1971 - 1987

Published: Jan. 19, 2024

Amyloid fibrils are known to be responsible for several neurological disorders, like Alzheimer's disease (AD), Parkinson's (PD), etc. For decades, mostly proteins and peptide-based amyloid have been focused on, the topic has acknowledged rise, development, understanding of, controversy, as well. However, single amino acid based fibrils, such phenylketonuria, tyrosenimia type II, hypermethioninemia, etc., gotten scientific attention lately. To understand molecular level pathogenesis of disorders originated due accumulation acid-based interaction these with phospholipid vesicle membranes is found an excellent cell-free in vitro setup. Based on setup, show a generic mechanism membrane insertion driven by electrostatic hydrophobic effects inside that reduces integral rigidity membrane. Alteration fundamental properties membrane, therefore, might referred one prime pathological factors development disorders. Hence, interactions must investigated cellular intracellular compartments design suitable therapeutic modulators against fibrils.

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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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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Exploring the Impact of C‐Terminal Based Pentapeptides on the Disassembly of Aβ₄₂ Fibrils

ChemMedChem, Journal Year: 2024, Volume and Issue: 19(22)

Published: July 18, 2024

Abstract An effective therapeutic strategy to suppress Alzheimer's disease (AD) progression is disrupt β‐sheet rich neurotoxic soluble amyloid‐β (Aβ) aggregates. Previously, we identified new pentapeptides (RVVPI and RIAPA) with notably enhanced ability block Aβ 42 aggregation as compared C‐terminal derived peptide RIIGL using integrated computational protocol. In this work, the potential of RIIGL, RVVPI, RIAPA for structural destabilization protofibril was assessed by molecular dynamics (MD) simulations in vitro studies. The binding free energy analysis depicts that charged residues influence protofibril‐pentapeptide interactions. Notably, RVVPI displays a more pronounced effect than other peptides due higher conformational fluctuations, disruption salt bridge (K28‐A42) interactions protofibril. exhibited highest inhibitory activity (Inhibition=66.2 %, IC 50 =5.57±0.83 μM) against consistent results. Remarkably, displayed ~4.5 fold lower value RIIGL. ThT TEM studies highlighted efficiency (62.4 %) disassembly pre‐formed fibrils RIAPA. combined silico peptide, an efficient inhibitor fibrillation

Language: Английский

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