A brief history of amyloid aggregation simulations

Wiley Interdisciplinary Reviews Computational Molecular Science, Journal Year: 2024, Volume and Issue: 14(1)

Published: Jan. 1, 2024

Abstract Amyloid proteins are characterized by their tendency to aggregate into amyloid fibrils, which often associated with devastating diseases. Aggregation pathways typically involve unfolding or misfolding of monomeric and formation transient oligomers protofibrils before the final aggregation product is formed. The conformational dynamics polymorphic volatile nature these intermediates make characterization experimental techniques alone insufficient also require computational approaches. Over past 25 years, size simulated systems length simulations have increased significantly. These advances discussed here. review includes simulation approaches that model aggregating peptides at both all‐atom coarse‐grained levels, use molecular Monte Carlo sampling simulate changes, present results for various ranging from Lys‐Phe‐Phe‐Glu (KFFE) as smallest system an intermediate‐sized peptide α‐synuclein. presentation history concludes a discussion where future may lie. This article categorized under: Structure Mechanism > Computational Biochemistry Biophysics Molecular Statistical Mechanics Dynamics Monte‐Carlo Methods

Language: Английский

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Selective recognition and discrimination of single isomeric changes in peptide strands with a host : guest sensing array

Chemical Science, Journal Year: 2024, Volume and Issue: 15(5), P. 1885 - 1893

Published: Jan. 1, 2024

A host : indicator array comprising cationic fluorophores and water-soluble receptors can selectively discriminate peptides containing a single isomeric residue in the backbone.

Language: Английский

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Precision proteoform design for 4R tau isoform selective templated aggregation

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(15)

Published: April 3, 2024

Prion-like spread of disease-specific tau conformers is a hallmark all tauopathies. A 19-residue probe peptide containing P301L mutation and spanning the R2/R3 splice junction folds stacks into seeding-competent fibrils induces aggregation 4R, but not 3R tau. These propagate aggregated intracellular over multiple generations, have high β-sheet content, colocalized lipid signal, adopt well-defined U-shaped fold found in 4R tauopathy brain-derived fibrils. Fully atomistic replica exchange molecular dynamics (MD) simulations were used to compute free energy landscapes conformational ensemble monomers. identified an aggregation-prohibiting β-hairpin structure aggregation-competent U-fold unique Guided by MD simulations, we that N-terminal-flanking residues PHF6, which slightly vary between isoforms, modulate seeding. Strikingly, when single amino acid switch at position 305 replaced serine with lysine from corresponding first repeat tau, seeding induced was markedly reduced. Conversely, mimic three repeats, prepared replacing those acids uniquely present second repeat, recovered exposed peptide. function as partial prions recruit naive tau—ten times length peptide—and serve critical template for propagation. results hint opportunities isoform–specific therapeutic interventions.

Language: Английский

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Hairpin trimer transition state of amyloid fibril

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: March 29, 2024

Abstract Protein fibril self-assembly is a universal transition implicated in neurodegenerative diseases. Although structure/growth are well characterized, nucleation poorly understood. Here, we use computational-experimental approach to resolve nucleation. We show that monomer hairpin content quantified from molecular dynamics simulations predictive of experimental formation kinetics across tau motif mutant library. Hairpin trimers predicted be states; one spontaneously converts into the cross-beta conformation, templating subsequent growth. designed disulfide-linked dimer mimicking state catalyzes formation, measured by ThT fluorescence and TEM, wild-type - which does not normally fibrillize. A compatible with extended conformations but transition-state fails nucleate at any concentration. Tau repeat domain how long-range interactions sequester this mutation-dependent manner. This work implies different morphologies could arise disease-dependent seeding loci.

Language: Английский

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Structures prediction and replica exchange molecular dynamics simulations of α-synuclein: A case study for intrinsically disordered proteins

International Journal of Biological Macromolecules, Journal Year: 2024, Volume and Issue: 276, P. 133813 - 133813

Published: Sept. 1, 2024

Language: Английский

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Perspective for Molecular Dynamics Simulation Studies of Amyloid-β Aggregates

The Journal of Physical Chemistry B, Journal Year: 2023, Volume and Issue: 127(51), P. 10931 - 10940

Published: Dec. 18, 2023

The cause of Alzheimer's disease is related to aggregates such as oligomers and amyloid fibrils consisting amyloid-β (Aβ) peptides. Molecular dynamics (MD) simulation studies have been conducted understand the molecular mechanism formation disruption Aβ aggregates. In this Perspective, MD are classified into four categories, focusing on target systems: aggregation peptides in bulk solution, at interface, inhibitor against peptides, nonequilibrium these categories first reviewed. Future perspectives each category then presented. Finally, overall perspective presented how simulations can be utilized for developing treatment.

Language: Английский

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A turn for the worse: Aβ β-hairpins in Alzheimer’s disease

Bioorganic & Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 105, P. 117715 - 117715

Published: April 11, 2024

Amyloid-β (Aβ) oligomers are a cause of neurodegeneration in Alzheimer's disease (AD). These soluble aggregates the Aβ peptide have proven difficult to study due their inherent metastability and heterogeneity. Strategies isolate stabilize homogenous oligomer populations emerged such as mutations, covalent cross-linking, protein fusions. strategies along with molecular dynamics simulations provided variety proposed structures oligomers, many which consist molecules β-hairpin conformations. β-Hairpins intramolecular antiparallel β-sheets composed two β-strands connected by loop or turn. Three decades research suggests that peptides form several different conformations, some building blocks toxic oligomers. The insights from these studies currently being used design anti-Aβ antibodies vaccines treat AD. Research antibody therapies designed target oligomeric may be more successful at treating AD than linear epitopes fibrillar Aβ. β-hairpins good use development selectively This review summarizes on discusses relevance this conformation pathogenesis drug development.

Language: Английский

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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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Sampling Conformational Ensembles of Highly Dynamic Proteins via Generative Deep Learning

Journal of Chemical Information and Modeling, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 21, 2025

Proteins are inherently dynamic, and their conformational ensembles play a crucial role in biological function. Large-scale motions may govern the protein structure–function relationship, numerous transient but stable conformations of intrinsically disordered proteins (IDPs) can Investigating to understand regulations disease-related aggregations IDPs is challenging, both experimentally computationally. In this paper, we first introduce deep learning-based model, termed Internal Coordinate Net (ICoN), which learns physical principles changes from molecular dynamics simulation data. Second, selected data points through interpolation learned latent space rapidly identify novel synthetic with sophisticated large-scale side chains backbone arrangements. Third, highly dynamic amyloid-β1–42 (Aβ42) monomer, our learning model provided comprehensive sampling Aβ42's landscape. Analysis these revealed clusters that could be used rationalize experimental findings. Additionally, method important interactions atomistic details not included training New showed distinct chain rearrangements probed by electron paramagnetic resonance amino acid substitution studies. This approach transferable for any available training. The work also demonstrated ability utilize natural conformation sampling.

Language: Английский

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Geometry based prediction of tau protein sites and motifs associated with misfolding and aggregation

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: March 25, 2025

Recent studies of tau proteins point to specific sites or motifs along the protein related its misfolding and aggregation propensity, which is associated with neurodegenerative diseases structure-dependent pathology. In this manuscript we employ topology geometry analyze local structure obtained from Protein Data Bank. Our results show that mathematical topology/geometry cryo-EM structures alone identify PGGG motifs, PHF6(*) as interest reveal a geometrical hierarchy differs for 3R+4R 4R tauopathies. By employing Local Topological Free Energy (LTE), find progressive supranuclear palsy (PSP) globular glial tauopathy (GGT) have highest LTE values around residues 302–305, are inside jR2R3 peptide in vicinity 301 site, experimentally aggregation. extending definition estimate global topological free energy, PSP GGT, has fact lowest energy among other These possible correlation between parts sites.

Language: Английский

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