scholarly journals Inactivation of Aβ42 Protomer-dimer Dissociation Reaction via Increasing Protomer Size

2021 ◽  
Author(s):  
Ikuo Kurisaki ◽  
Shigenori Tanaka
Keyword(s):  
Molecular Mechanisms ◽  
Amyloid Fibril ◽  
Amyloid Β ◽  
Minimum Size ◽  
Molecular Entity ◽  
Human Beings ◽  
Dimer Formation ◽  
Mean Lifetime ◽  
Conformational Fluctuation ◽  
Dynamics Simulations

AbstractAmyloid fibril growth is supposed to be common pathogenic causes for neurodegenerative diseases, triggered by sufficient amounts of growth nuclei species. Since the molecular entity of growth nuclei is regarded as fibril-like aggregates, clarifying the minimum size of thermodynamically stable fibril-like aggregates has been a long standing problem to understand molecular mechanisms of amyloid fibril growth. We studied this problem by examining relationship between the size of fibril-like amyloid-β(1-42) (Aβ42) aggregates and their thermodynamic stability. Seven different protomer dimers were examined as Aβ42 fibril-like aggregate models with employing atomistic molecular dynamics simulations. This study has found that increase of protomer size suppresses conformational fluctuation of these aggregates and inactivates protomer-protomer dissociation reactions by making timescales much longer than mean lifetime of human beings at the point of pentamer dimer formation. This observation shows apparent contribution of protomer size to stabilization of fibril-like aggregates, thus implying that dimer formation of relatively small protomers is a turning point toward growth nuclei formation. Meanwhile, Aβ42 monomer dissociation from the edges of protomers can occur within timescales ranging from microsecond to second and could work for Aβ42 protomer decomposition. This observation implies that suppressing the decomposition route leads to stable Aβ42 growth nuclei formation.

scholarly journals An evaluation of the self-assembly enhancing properties of cell-derived hexameric amyloid-β

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Devkee M. Vadukul ◽  
Céline Vrancx ◽  
Pierre Burguet ◽  
Sabrina Contino ◽  
Nuria Suelves ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Self Assembly ◽  
Critical Nucleus ◽  
Amyloid Fibril ◽  
Amyloid Β ◽  
Amyloid Plaques ◽  
The Self ◽  
Aβ Peptide ◽  
Amyloid Fibril Formation ◽  
Secretase Activity

AbstractA key hallmark of Alzheimer’s disease is the extracellular deposition of amyloid plaques composed primarily of the amyloidogenic amyloid-β (Aβ) peptide. The Aβ peptide is a product of sequential cleavage of the Amyloid Precursor Protein, the first step of which gives rise to a C-terminal Fragment (C99). Cleavage of C99 by γ-secretase activity releases Aβ of several lengths and the Aβ42 isoform in particular has been identified as being neurotoxic. The misfolding of Aβ leads to subsequent amyloid fibril formation by nucleated polymerisation. This requires an initial and critical nucleus for self-assembly. Here, we identify and characterise the composition and self-assembly properties of cell-derived hexameric Aβ42 and show its assembly enhancing properties which are dependent on the Aβ monomer availability. Identification of nucleating assemblies that contribute to self-assembly in this way may serve as therapeutic targets to prevent the formation of toxic oligomers.

Insights into the roles of charged residues in substrate binding and mode of action of mannuronan C-5 epimerase AlgE4

Glycobiology ◽  
2021 ◽  
Author(s):  
Margrethe Gaardløs ◽  
Sergey A Samsonov ◽  
Marit Sletmoen ◽  
Maya Hjørnevik ◽  
Gerd Inger Sætrom ◽  
...  
Keyword(s):  
Optical Tweezers ◽  
Conformational Changes ◽  
Molecular Mechanisms ◽  
Hydrophobic Interactions ◽  
Substrate Binding ◽  
Interdisciplinary Approach ◽  
Product Formation ◽  
Titration Calorimetry ◽  
Binding Groove ◽  
Dynamics Simulations

Abstract Mannuronan C-5 epimerases catalyse the epimerization of monomer residues in the polysaccharide alginate, changing the physical properties of the biopolymer. The enzymes are utilized to tailor alginate to numerous biological functions by alginate-producing organisms. The underlying molecular mechanisms that control the processive movement of the epimerase along the substrate chain is still elusive. To study this, we have used an interdisciplinary approach combining molecular dynamics simulations with experimental methods from mutant studies of AlgE4, where initial epimerase activity and product formation were addressed with NMR spectroscopy, and characteristics of enzyme-substrate interactions were obtained with isothermal titration calorimetry and optical tweezers. Positive charges lining the substrate-binding groove of AlgE4 appear to control the initial binding of poly-mannuronate, and binding also seems to be mediated by both electrostatic and hydrophobic interactions. After the catalytic reaction, negatively charged enzyme residues might facilitate dissociation of alginate from the positive residues, working like electrostatic switches, allowing the substrate to translocate in the binding groove. Molecular simulations show translocation increments of two monosaccharide units before the next productive binding event resulting in MG-block formation, with the epimerase moving with its N-terminus towards the reducing end of the alginate chain. Our results indicate that the charge pair R343-D345 might be directly involved in conformational changes of a loop that can be important for binding and dissociation. The computational and experimental approaches used in this study complement each other, allowing for a better understanding of individual residues’ roles in binding and movement along the alginate chains.

scholarly journals Snails In Silico: A Review of Computational Studies on the Conopeptides

Marine Drugs ◽  
2019 ◽  
Vol 17 (3) ◽  
pp. 145 ◽  
Author(s):  
Rachael Mansbach ◽  
Timothy Travers ◽  
Benjamin McMahon ◽  
Jeanne Fair ◽  
S. Gnanakaran
Keyword(s):  
Posttranslational Modifications ◽  
High Throughput Screening ◽  
Molecular Mechanisms ◽  
Defense Mechanism ◽  
Docking Studies ◽  
Chemical Diversity ◽  
Machine Learning Techniques ◽  
Peptide Toxins ◽  
Dynamics Simulations ◽  
And Function

Marine cone snails are carnivorous gastropods that use peptide toxins called conopeptides both as a defense mechanism and as a means to immobilize and kill their prey. These peptide toxins exhibit a large chemical diversity that enables exquisite specificity and potency for target receptor proteins. This diversity arises in terms of variations both in amino acid sequence and length, and in posttranslational modifications, particularly the formation of multiple disulfide linkages. Most of the functionally characterized conopeptides target ion channels of animal nervous systems, which has led to research on their therapeutic applications. Many facets of the underlying molecular mechanisms responsible for the specificity and virulence of conopeptides, however, remain poorly understood. In this review, we will explore the chemical diversity of conopeptides from a computational perspective. First, we discuss current approaches used for classifying conopeptides. Next, we review different computational strategies that have been applied to understanding and predicting their structure and function, from machine learning techniques for predictive classification to docking studies and molecular dynamics simulations for molecular-level understanding. We then review recent novel computational approaches for rapid high-throughput screening and chemical design of conopeptides for particular applications. We close with an assessment of the state of the field, emphasizing important questions for future lines of inquiry.

Destabilization of Alzheimer’s Aβ42 protofibrils with acyclovir, carmustine, curcumin, and tetracycline: Insights from molecular dynamics simulations

2021 ◽  
Author(s):  
Ishrat Jahan ◽  
Shahid M Nayeem
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Dynamics ◽  
Neurodegenerative Diseases ◽  
Molecular Dynamics Simulations ◽  
Amyloid Β ◽  
Neural Tissue ◽  
Amyloid Β Peptide ◽  
Characteristic Symptom ◽  
Dynamics Simulations

One of the most common dementia among neurodegenerative diseases is Alzheimer’s disease (AD). The characteristic symptom of AD is the deposition and aggregation of amyloid-β-peptide in the neural tissue. A...

scholarly journals Molecular dynamics simulations of mechanical failure in polymorphic arrangements of amyloid fibrils containing structural defects

2013 ◽  
Vol 4 ◽  
pp. 429-440 ◽  
Author(s):  
Hlengisizwe Ndlovu ◽  
Alison E Ashcroft ◽  
Sheena E Radford ◽  
Sarah A Harris
Keyword(s):  
Mechanical Properties ◽  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Amyloid Fibrils ◽  
Amyloid Fibril ◽  
Steered Molecular Dynamics ◽  
Mechanical Failure ◽  
Structural Defects ◽  
Dynamics Simulations

We examine how the different steric packing arrangements found in amyloid fibril polymorphs can modulate their mechanical properties using steered molecular dynamics simulations. Our calculations demonstrate that for fibrils containing structural defects, their ability to resist force in a particular direction can be dominated by both the number and molecular details of the defects that are present. The simulations thereby suggest a hierarchy of factors that govern the mechanical resilience of fibrils, and illustrate the general principles that must be considered when quantifying the mechanical properties of amyloid fibres containing defects.

scholarly journals The Impact of Medium Chain and Polyunsaturated ω-3-Fatty Acids on Amyloid-β Deposition, Oxidative Stress and Metabolic Dysfunction Associated with Alzheimer´s Disease

Antioxidants ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1991
Author(s):  
Janine Mett
Keyword(s):  
Oxidative Stress ◽  
Fatty Acids ◽  
Energy Metabolism ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Membrane Integrity ◽  
Amyloid Β ◽  
The Elderly ◽  
Medium Chain ◽  
The Impact

Alzheimer’s disease (AD), the most common cause of dementia in the elderly population, is closely linked to a dysregulated cerebral lipid homeostasis and particular changes in brain fatty acid (FA) composition. The abnormal extracellular accumulation and deposition of the peptide amyloid-β (Aβ) is considered as an early toxic event in AD pathogenesis, which initiates a series of events leading to neuronal dysfunction and death. These include the induction of neuroinflammation and oxidative stress, the disruption of calcium homeostasis and membrane integrity, an impairment of cerebral energy metabolism, as well as synaptic and mitochondrial dysfunction. Dietary medium chain fatty acids (MCFAs) and polyunsaturated ω-3-fatty acids (ω-3-PUFAs) seem to be valuable for disease modification. Both classes of FAs have neuronal health-promoting and cognition-enhancing properties and might be of benefit for patients suffering from mild cognitive impairment (MCI) and AD. This review summarizes the current knowledge about the molecular mechanisms by which MCFAs and ω-3-PUFAs reduce the cerebral Aβ deposition, improve brain energy metabolism, and lessen oxidative stress levels.

scholarly journals Molecular mechanisms associated with clustered lesion-induced impairment of 8-oxoG recognition by the human glycosylase OGG1

2021 ◽  
Author(s):  
Tao Jiang ◽  
Antonio MONARI ◽  
Elise Dumont ◽  
Emmanuelle Bignon
Keyword(s):  
Protein Interactions ◽  
Molecular Mechanisms ◽  
Excision Repair ◽  
Structural Features ◽  
Repair Pathway ◽  
Dna Lesion ◽  
Damage Response ◽  
Base Excision ◽  
Structural Signature ◽  
Dynamics Simulations

The 8-oxo-7,8-dihydroguanine, referred to as 8-oxoG, is a highly mutagenic DNA lesion that can provoke the appearance of mismatches if it escapes the DNA Damage Response. The specific recognition of its structural signature by the hOGG1 glycosylase is the first step along the Base Excision Repair pathway, that ensures the integrity of the genome by preventing the emergence of mutations. 8-oxoG formation, structural features and repair have been the matter of extensive research and more recently this active field of research expended to the more complicated case of 8-oxoG within clustered lesions. Indeed, the presence of a second lesion within 1 or 2 helix turns can dramatically impact the repair yields of 8-oxoG by glycosylases. In this work, we use mu-range molecular dynamics simulations and machine learning-based post-analysis to explore the molecular mechanisms associated with the recognition of 8-oxoG by hOGG1 when embedded in a multiple lesions site with a mismatch in 5' or 3'. We delineate the stiffening of the DNA-protein interactions upon the presence of the mismatches, and rationalize the much lower repair yields reported with a 5' mismatch by describing the perturbation of 8-oxoG structural features upon addition of an adjacent lesion.

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