The Journal of Physical Chemistry B, Год журнала: 2024, Номер unknown
Опубликована: Дек. 4, 2024
The association of 55 dipeptides extracted from aggregation-prone regions selected proteins was studied by means multiplexed replica-exchange molecular dynamics simulations with the coarse-grained UNRES model polypeptide chains. Each simulation carried out 320 dipeptide molecules in a periodic box at 0.24 mol/dm
Язык: Английский
bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown
Опубликована: Июль 17, 2024
Abstract In classical amyloidoses, amyloid fibres form through the nucleation and accretion of protein monomers, with protofibrils fibrils exhibiting a cross-β motif parallel or antiparallel β-sheets oriented perpendicular to fibre direction. These can intertwine mature fibres. Similar phenomena occur in blood from individuals circulating inflammatory molecules (also those originating viruses bacteria). presence inflammagens, pathological clotting occur, that results an anomalous termed fibrinaloid microclots. Previous proteomic analyses these microclots have shown non-fibrin(ogen) proteins, suggesting more complex mechanism than simple entrapment. We provide evidence against entrapment model, noting clot pores are too large centrifugation would removed weakly bound proteins. Instead, we explore whether co-aggregation into may involve axial (multiple proteins within same fibril), lateral (single-protein contributing fibre), both types integration. Our analysis data different diseases shows no significant overlap normal plasma proteome correlation between abundance Notably, abundant like α-2-macroglobulin, fibronectin, transthyretin absent microclots, while less such as adiponectin, periostin, von Willebrand Factor well represented. Using bioinformatic tools including AmyloGram AnuPP, found entrapped exhibit high amyloidogenic tendencies, their integration elements structures. This likely contributes microclots’ resistance proteolysis. findings underscore role cross-seeding microclot formation highlight need for further investigation structural properties implications thrombotic diseases. insights foundation developing novel diagnostic therapeutic strategies targeting disorders.
Язык: Английский
Процитировано
3
Biochemical and Biophysical Research Communications, Год журнала: 2025, Номер 758, С. 151652 - 151652
Опубликована: Март 17, 2025
Язык: Английский
Процитировано
0
Protein Science, Год журнала: 2025, Номер 34(6)
Опубликована: Май 15, 2025
Abstract This study provides critical insights into the role of surface‐mediated processes in Alzheimer's disease, with implications for aggregation Abeta42 peptides. Employing coarse‐grained molecular dynamics simulations, we focus on elucidating intricacies these beyond primary nucleation. Central to our investigation is analysis a freely diffusing monomer preformed fibril structures. We conduct detailed calculations monomer's diffusion coefficient surfaces (as one‐dimensional case), along various orientations. Our findings reveal strong and consistent correlation between its orientation surface. Further differentiates effects parallel perpendicular alignments respect axis. Additionally, explore how different influence by comparing C‐terminal N‐terminal surfaces. find that exhibits faster coefficients Differences surface roughness ( S R ), quantified using root‐mean‐square distances, significantly affect dynamics, thereby influencing Importantly, this underscores twisting acts as regulatory niche, selectively orientations their properties necessary facilitating growth within biologically relevant time scales. discovery opens new avenues targeted therapeutic strategies aimed at manipulating mitigate progression disease.
Язык: Английский
Процитировано
0
Small Science, Год журнала: 2024, Номер unknown
Опубликована: Июнь 22, 2024
Aggregation of the amyloid β (Aβ) peptide into fibrils represents one major biochemical pathways underlying development Alzheimer's disease (AD). Extensive studies have been carried out to understand role fibrillar seeds on overall kinetics aggregation. However, precise effect that are structurally or sequentially different from Aβ structure resulting aggregates is yet be fully understood. Herein, nanoscale infrared spectroscopy used probe spectral facets individual formed by aggregating Aβ42 with antiparallel Aβ(16–22) and E22Q Aβ(1–40) Dutch mutant it demonstrated can form heterotypic mixed polymorphs deviate significantly its expected parallel cross structure. It further shown formation not limited coaggregation isomers, former alpha‐synuclein brain protein lysates. These findings highlight complexity aggregation in AD underscore need explore how interacts other components, which crucial for developing better therapeutic strategies AD.
Язык: Английский
Процитировано
2
International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(19), С. 10809 - 10809
Опубликована: Окт. 8, 2024
In classical amyloidoses, amyloid fibres form through the nucleation and accretion of protein monomers, with protofibrils fibrils exhibiting a cross-β motif parallel or antiparallel β-sheets oriented perpendicular to fibre direction. These can intertwine mature fibres. Similar phenomena occur in blood from individuals circulating inflammatory molecules (and also some originating viruses bacteria). Such pathological clotting result an anomalous termed fibrinaloid microclots. Previous proteomic analyses these microclots have shown presence non-fibrin(ogen) proteins, suggesting more complex mechanism than simple entrapment. We thus provide evidence against such entrapment model, noting that clot pores are too large centrifugation would removed weakly bound proteins. Instead, we explore whether co-aggregation into may involve axial (multiple proteins within same fibril), lateral (single-protein contributing fibre), both types integration. Our analysis data different diseases shows no significant quantitative overlap normal plasma proteome correlation between abundance their Notably, abundant like α-2-macroglobulin, fibronectin, transthyretin absent microclots, while less as adiponectin, periostin, von Willebrand factor well represented. Using bioinformatic tools, including AmyloGram AnuPP, found entrapped exhibit high amyloidogenic tendencies, integration elements structures. This likely contributes microclots’ resistance proteolysis. findings underscore role cross-seeding microclot formation highlight need for further investigation structural properties implications thrombotic diseases. insights foundation developing novel diagnostic therapeutic strategies targeting disorders.
Язык: Английский
Процитировано
2
Biophysical Reviews, Год журнала: 2024, Номер 16(6), С. 701 - 722
Опубликована: Ноя. 20, 2024
Язык: Английский
Процитировано
1
The Journal of Physical Chemistry B, Год журнала: 2024, Номер 128(41), С. 9947 - 9958
Опубликована: Окт. 4, 2024
The accumulation of amyloid-beta (
Язык: Английский
Процитировано
0
Chemical Communications, Год журнала: 2024, Номер unknown
Опубликована: Янв. 1, 2024
The energy landscape of monomeric amyloid-β peptides is characterised by a funnel leading to disorder; upon dimerisation, it transforms folding towards stabilised β-hairpin, which significant in the context Alzheimer's disease.
Язык: Английский
Процитировано
0
Journal of Chemical Information and Modeling, Год журнала: 2024, Номер 64(22), С. 8628 - 8640
Опубликована: Окт. 30, 2024
Amyloids, large intermolecular sandwiched β-sheet structures, underlie several protein misfolding diseases but have also been shown to functional roles and can be a basis for designing smart responsive nanomaterials. Short segments of proteins, called aggregation-prone regions (APRs), identified that nucleate amyloid formation. Here we present the database 173 APR crystal structures currently available in PDB, tool, ACW, analyzing their topologies 267 inter-β-sheet interfaces zipper assigned these structures. We defined new descriptor interfaces, surface detail index (SDi), which quantifies intertwining between side chains both β-sheets zipper, an important factor molecular recognition self-assembly mesostructures. This allowed comparative analysis identification 6 clusters with different intertwining, steric fit, size characteristics using three complementary descriptors, SDi, shape complementarity, buried area. 60% are formed by parallel β-sheets, 52% belong topological class 1. could explained better fit deeper entanglement than antiparallel as showed complementarity (0.79 vs 0.70) SDi (1.53 1.32) were higher. The higher abundance certain residues (Asn Gln Leu Ala β-sheets) ability form ladder-like secondary interaction patterns within β-sheets. Analogous hierarchy structure, interpreted primary, secondary, tertiary, quaternary structure levels APRs revealing may provide clues structural conditions core formation rational design polymorphs.
Язык: Английский
Процитировано
0
The Journal of Physical Chemistry B, Год журнала: 2024, Номер unknown
Опубликована: Дек. 4, 2024
The association of 55 dipeptides extracted from aggregation-prone regions selected proteins was studied by means multiplexed replica-exchange molecular dynamics simulations with the coarse-grained UNRES model polypeptide chains. Each simulation carried out 320 dipeptide molecules in a periodic box at 0.24 mol/dm
Язык: Английский
Процитировано
0