Molecular Dynamics Simulations of the Tau R3–R4 Domain Monomer in the Bulk Solution and at the Surface of a Lipid Bilayer Model

The Journal of Physical Chemistry B, Journal Year: 2022, Volume and Issue: 126(18), P. 3431 - 3438

Published: April 27, 2022

The aggregation of the tau protein plays a significant role in Alzheimer's disease, and R3–R4 domain spanning residues 306–378 was shown to form amyloid fibril core full-length tau. conformations monomer bulk solution at surface membranes are unknown. In this study, we address these questions by means atomistic molecular dynamics. simulations show very heterogeneous ensemble with low β helical contents. has propensity transient β-hairpins within R3 repeat between R4 repeats parallel β-sheets repeats. also that membrane does not induce β-sheet insertion leads an structures different from those solution. They reveal dynamical properties membrane-bound state monomer, enabling 306–318 376–378.

Language: Английский

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Critical micellar concentration determination of pure phospholipids and lipid‐raft and their mixtures with cholesterol

Proteins Structure Function and Bioinformatics, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 17, 2024

Abstract Phospholipids in biological membranes establish a chemical equilibrium between free phospholipids the aqueous phase (CMC) and self‐assembled vesicles, keeping CMC constant. The is different for each phospholipid, depends on amount of cholesterol, and, according to lipid‐chaperone hypothesis, controls interaction amyloidogenic proteins (such as amylin, amyloid‐β, α‐synuclein, all which are, respectively, associated with proteinopathy), governs formation toxic complex lipids that leads membrane destruction. Here, we provide quantitative measurements CMCs bilayer stability pure phospholipids, lipid rafts, their mixture cholesterol by fluorescence methods (using pyrene probe) light scattering techniques (resonance Rayleigh fixed‐angle scattering) performed LUVs, well AFM measure LUV dimensions. Also, test hypothesis human IAPP interacting POPC cholesterol. Stated importance protein aggregation processes, these results could be starting point development kinetic model chaperone hypothesis.

Language: Английский

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Understanding Aβ Peptide Binding to Lipid Membranes: A Biophysical Perspective

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(12), P. 6401 - 6401

Published: June 10, 2024

Aβ peptides are known to bind neural plasma membranes in a process leading the deposit of Aβ-enriched plaques. These extracellular structures characteristic Alzheimer's disease, major cause late-age dementia. The mechanisms plaque formation and deposition far from being understood. A vast number studies literature describe efforts analyze those using variety tools. present review focuses on biophysical mostly carried out with model or computational This starts by describing basic physical aspects lipid phases commonly used (monolayers bilayers). is followed discussion techniques applied these systems, mainly but not exclusively Langmuir monolayers, isothermal calorimetry, density-gradient ultracentrifugation, molecular dynamics. Methodological Section core review, which includes summary important results obtained each technique. last section devoted an overall reflection effort understand Aβ-bilayer binding. Concepts such as peptide membrane binding, adsorption, insertion defined differentiated. roles order, nanodomain formation, electrostatic forces Aβ-membrane interaction separately identified discussed.

Language: Английский

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Effects of Redox Homeostasis and Mitochondrial Damage on Alzheimer’s Disease

Antioxidants, Journal Year: 2023, Volume and Issue: 12(10), P. 1816 - 1816

Published: Sept. 30, 2023

Bioenergetic mitochondrial dysfunction is a common feature of several diseases, including Alzheimer’s disease (AD), where redox imbalance also plays an important role in terms development. AD age-related and begins many years before the appearance neurodegenerative symptoms. Intracellular tau aggregation, extracellular β-amyloid (Aβ) deposition brain, even APOE4 genotype contribute to process by impairing homeostasis dysfunction. This review summarizes evidence for demonstrates current therapeutic strategies related maintenance.

Language: Английский

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β-Amyloids and Immune Responses Associated with Alzheimer’s Disease

Cells, Journal Year: 2024, Volume and Issue: 13(19), P. 1624 - 1624

Published: Sept. 28, 2024

Alzheimer’s disease (AD) is associated with the accumulation of β-amyloids (Aβs) and formation Aβ plaques in brain. Various structural forms isoforms Aβs that have variable propensities for oligomerization toxicity may differentially affect development AD been identified. In addition, there evidence are engaged complex interactions innate adaptive immune systems, both which also play a role regulation onset progression. this review, we discuss what currently known about intricate interplay between response to more in-depth focus on possible roles B cells pathogenesis AD.

Language: Английский

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Scan-Find-Scan-Model: Discrete Site-Targeted Suppressor Design Strategy for Amyloid-β

ACS Chemical Neuroscience, Journal Year: 2022, Volume and Issue: 13(14), P. 2191 - 2208

Published: June 29, 2022

Alzheimer's disease is undoubtedly the most well-studied neurodegenerative disease. Consequently, amyloid-β (Aβ) protein ranks at top in terms of getting attention from scientific community for structural property-based characterization. Even after decades extensive research, there existing volatility understanding and hence effective tackling procedures against that arises due to lack knowledge both specific target- site-specific drugs. Here, we develop a multidimensional approach based on characterization common static-dynamic-thermodynamic trait monomeric protein, which efficiently identifies small target sequence contains an inherent tendency misfold consequently aggregate. The robustness identification comes with abundance priori about length guides toward designing target-specific drug very low probability bottleneck failure. Based information, further identified mutant showed maximum potential act as destabilizer well enormous success aggregation suppressor. We eventually tested efficacy by estimating extent modulation binding affinity within fibrillar form Aβ single-point mutation provided proof concept entire protocol.

Language: Английский

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Library-Derived Peptide Aggregation Modulators of Parkinson’s Disease Early-Onset α-Synuclein Variants

ACS Chemical Neuroscience, Journal Year: 2022, Volume and Issue: 13(12), P. 1790 - 1804

Published: May 25, 2022

Parkinson's Disease (PD) is characterized by the accumulation of Lewy bodies in dopaminergic neurons. The main protein component bodies, α-synuclein (αS), also firmly linked to PD through identification a number single point mutations that are autosomal dominant for early-onset disease. Consequently, misfolding and subsequent aggregation αS thought be key stage development progression PD. Therefore, modulating pathway an attractive therapeutic target. Owing fact all but one familial located preNAC 45–54 region αS, we previously designed semi-rational library using this sequence as design scaffold. peptide was screened protein-fragment complementation assay approach, leading 4554W peptide. subsequently found effective inhibiting primary nucleation earliest pathway. Here, build upon previous work screening same against five known single-point mutants associated with (A30P, E46K, H50Q, G51D, A53T). These lead rapid acceleration pathology altering either rate or type aggregates formed. All ultimately earlier disease onset were therefore used enforce increased stringency during process. ultimate aim identify not only variant from which it has been selected WT αS. Screening resulted peptides shared common residues at some positions, while deviating others. reduced respective target, several identified reducing when incubated other variants. In addition, our results demonstrate optimized peptide, 4554W(N6A), highly mutant forms hence suitable baseline further toward therapeutic.

Language: Английский

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Differential Effects of Ganglioside Lipids on the Conformation and Aggregation of Islet Amyloid Polypeptide

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 31, 2024

ABSTRACT Despite causing over 1 million deaths annually, Type 2 Diabetes (T2D) currently has no curative treatments. Aggregation of the islet amyloid polypeptide (hIAPP) into plaques plays an important role in pathophysiology T2D and thus presents a target for therapeutic intervention. The mechanism by which hIAPP aggregates contributes to development is unclear but are proposed involve disruption cellular membranes. However, nearly all research on hIAPP-lipid interactions focused anionic phospholipids, primarily present cytosolic face plasma We seek here characterize effects three gangliosides, dominant lipids outer leaflet membrane, aggregation, structure, toxicity hIAPP. Our results show dual behavior that depends molar ratio between gangliosides For each ganglioside, low lipid:peptide enhances aggregation alters morphology fibrils, while high eliminates stabilizes α-helix-rich conformation. A more negative lipid charge efficiently promotes larger headgroup improves inhibition aggregation. also phase transitions lipids, favoring spherical micelles tubular micelles. discuss our context available surface area binding speculate facilitating toxic

Language: Английский

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Production of Distinct Fibrillar, Oligomeric, and Other Aggregation States from Network Models of Multibody Interaction

Journal of Chemical Theory and Computation, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 11, 2024

Protein aggregation can produce a wide range of states, ranging from fibrillar structures and oligomers to unstructured semistructured gel phases. Recent work has shown that many these states be recapitulated by relatively simple, topological models specified in terms multibody interaction energies, providing direct connection between aggregate intermolecular forces products. Here, we examine low-dimensional network Hamiltonian model (NHM) based on four basic interactions found any system. We characterize the phase behavior this NHM family, showing fibrils arise balance elongation-inducing contact-inhibiting forces. Complex (including annular resembling those thought toxic species Alzheimer's disease) also form distinct phases regime, controlled part closure-inducing show structure is largely independent system size, provide evidence rich minor oligomeric appropriate conditions. demonstrating ordered disordered possible with set interactions. As show, forces, existing regime bounded gel-like disaggregated phases; complex allowing generalization macroscopic systems,

Language: Английский

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Differential effects of ganglioside lipids on the conformation and aggregation of islet amyloid polypeptide

Protein Science, Journal Year: 2024, Volume and Issue: 33(8)

Published: July 16, 2024

Despite causing over 1 million deaths annually, Type 2 Diabetes (T2D) currently has no curative treatments. Aggregation of the islet amyloid polypeptide (hIAPP) into plaques plays an important role in pathophysiology T2D and thus presents a target for therapeutic intervention. The mechanism by which hIAPP aggregates contribute to development is unclear, but it proposed involve disruption cellular membranes. However, nearly all research on hIAPP-lipid interactions focused anionic phospholipids, are primarily present cytosolic face plasma We seek here characterize effects three gangliosides, dominant lipids outer leaflet membrane, aggregation, structure, toxicity hIAPP. Our results show dual behavior that depends molar ratio between gangliosides For each ganglioside, low-lipid:peptide enhances aggregation alters morphology fibrils, while high eliminates stabilizes α-helix-rich conformation. A more negative lipid charge efficiently promotes larger headgroup improves inhibition aggregation. also phase transitions lipids, favoring spherical micelles tubular micelles. discuss our context available surface area binding speculate facilitating toxic

Language: Английский

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