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Recent Advances in Molecular Dynamics Simulations of Tau Fibrils and Oligomers.

ABSTRACT: The study of tau protein aggregation and interactions with other molecules or solvents using molecular dynamics simulations (MDs) is of interest to many researchers to propose new mechanism-based therapeutics for neurodegenerative diseases such as Alzheimer's disease, Pick's disease, chronic traumatic encephalopathy, and other tauopathies. In this review, we present recent MD simulation studies of tau oligomers and fibrils such as tau-NPK, tau-PHF, tau-K18, and tau-R3-R4 monomers and dimers. All-atom simulations by replica exchange MDs and coarse-grained MDs in lipid bilayers and in solution were used. The simulations revealed different mechanisms in the binding of tau in bilayers and in solutions, depending on the peptide size. Phosphorylation is also an important factor in MD simulations. The use of steered MDs was also included to simulate the dissociation of tau fibrils. The exponential improvement in the computing power of computers has led to an increasing number of scientists and engineers using a cost-effective, high-performance computing platform to study how the tau protein interacts and the effects of changing its structure, such as the phosphorylation of tau fibrils.

SUBMITTER: Barredo PA

PROVIDER: S-EPMC10052016 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Recent Advances in Molecular Dynamics Simulations of Tau Fibrils and Oligomers.

Barredo Prechiel A PA Balanay Mannix P MP

Membranes 20230226 3

The study of tau protein aggregation and interactions with other molecules or solvents using molecular dynamics simulations (MDs) is of interest to many researchers to propose new mechanism-based therapeutics for neurodegenerative diseases such as Alzheimer's disease, Pick's disease, chronic traumatic encephalopathy, and other tauopathies. In this review, we present recent MD simulation studies of tau oligomers and fibrils such as tau-NPK, tau-PHF, tau-K18, and tau-R3-R4 monomers and dimers. All ...[more]

PMID: 36984665

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Project description:The aggregation of amyloid-β (Aβ) peptides into senile plaques is a hallmark of Alzheimer's disease (AD) and is hypothesized to be the primary cause of AD related neurodegeneration. Previous studies have shown the ability of curcumin to both inhibit the aggregation of Aβ peptides into oligomers or fibrils and reduce amyloids in vivo. Despite the promise of curcumin and its derivatives to serve as diagnostic, preventative, and potentially therapeutic AD molecules, the mechanism by which curcumin and its derivatives bind to and inhibit Aβ fibrils' formation remains elusive. Here, we investigated curcumin and a set of curcumin derivatives in complex with a hexamer peptide model of the Aβ1-42 fibril using nearly exhaustive docking, followed by multi-ns molecular dynamics simulations, to provide atomistic-detail insights into the molecules' binding and inhibitory properties. In the vast majority of the simulations, curcumin and its derivatives remain firmly bound in complex with the fibril through primarily three different principle binding modes, in which the molecules interact with residue domain 17LVFFA21, in line with previous experiments. In a small subset of these simulations, the molecules partly dissociate the outermost peptide of the Aβ1-42 fibril by disrupting β-sheets within the residue domain 12VHHQKLVFF20. A comparison between binding modes leading or not leading to partial dissociation of the outermost peptide suggests that the latter is attributed to a few subtle key structural and energetic interaction-based differences. Interestingly, partial dissociation appears to be either an outcome of high affinity interactions or a cause leading to high affinity interactions between the molecules and the fibril, which could partly serve as a compensation for the energy loss in the fibril due to partial dissociation. In conjunction with this, we suggest a potential inhibition mechanism of Αβ1-42 aggregation by the molecules, where the partially dissociated 16KLVFF20 domain of the outermost peptide could either remain unstructured or wrap around to form intramolecular interactions with the same peptide's 29GAIIG33 domain, while the molecules could additionally act as a patch against the external edge of the second outermost peptide's 16KLVFF20 domain. Thereby, individually or concurrently, these could prohibit fibril elongation.

Project description:Aggregation of β-amyloid (Aβ) peptide is one of the hallmarks of Alzheimer's disease (AD) which results in chronic and progressive neurodegeneration of the brain. A recent study by our group have shown the ability of cyclic disulfide-rich peptides ("cyclotides") isolated from a medicinal plant, Clitoria ternatea, to inhibit the aggregation of Aβ peptides and reduce oxidative stress caused by reactive oxygen species using in vivo models of transgenic Caenorhabditis elegans. In the present study, through extensive computational docking and multi-ns molecular dynamics (MD) simulation, we evaluated if cyclotides can stably bind to Aβ molecules and/or destabilize the Aβ fibril by preventing conformational changes from α-helical to β-sheet rich structures. We demonstrate that cyclotides bind effectively and stably to different forms of Aβ structures via hydrogen bonding and hydrophobic interactions. One of the conserved hydrophobic interface residues, Tyr10 was mutated to Ala and the impact of this virtual mutation was estimated by additional MD simulations for the wild-type (WT) and mutant protein-peptide complexes. A detailed MD simulation analyses revealed that cyclotides form hydrogen bonds with the toxic amyloid assemblies thereby weakening the inter-strand hydrogen bonds between the Aβ peptide. The φ-ѱ distribution map of residues in the cyclotide binding pocket that ideally adopt β-sheet conformation show deviation towards right-handed ɑ-helical (ɑR) conformation. This effect was similar to that observed for the Tyr10Ala mutant and doubly so, for the cyclotide bound form. It is therefore possible to hypothesise that the opening up of amyloid β-sheet is due to an unfolding process occurring in the Aβ caused by cyclotide binding and inhibition. Our current findings provide novel structural insights on the mode of interaction between cyclotides and Aβ fibrils and describe their anti-amyloid aggregation potential. This sheds light on the future of cyclotide-based drug design against protein aggregation, a hallmark event in many neurodegenerative diseases.

Dataset Information

Recent Advances in Molecular Dynamics Simulations of Tau Fibrils and Oligomers.

Publications

Recent Advances in Molecular Dynamics Simulations of Tau Fibrils and Oligomers.

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