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Insight Into Seeded Tau Fibril Growth From Molecular Dynamics Simulation of the Alzheimer's Disease Protofibril Core.

ABSTRACT: Aggregates of the microtubule associated tau protein are a major constituent of neurofibrillary lesions that define Alzheimer's disease (AD) pathology. Increasing experimental evidence suggests that the spread of tau neurofibrillary tangles results from a prion-like seeding mechanism in which small oligomeric tau fibrils template the conversion of native, intrinsically disordered, tau proteins into their pathological form. By using atomistic molecular dynamics (MD) simulations, we investigate the stability and dissociation thermodynamics of high-resolution cryo-electron microscopy (cryo-EM) structures of both the AD paired-helical filament (PHF) and straight filament (SF). Non-equilibrium steered MD (SMD) center-of-mass pulling simulations are used to probe the stability of the protofibril structure and identify intermolecular contacts that must be broken before a single tau peptide can dissociate from the protofibril end. Using a combination of exploratory metadynamics and umbrella sampling, we investigate the complete dissociation pathway and compute a free energy profile for the dissociation of a single tau peptide from the fibril end. Different features of the free energy surface between the PHF and SF protofibril result from a different mechanism of tau unfolding. Comparison of wild-type tau PHF and post-translationally modified pSer356 tau shows that phosphorylation at this site changes the dissociation free energy surface of the terminal peptide. These results demonstrate how different protofibril morphologies template the folding of endogenous tau in distinct ways, and how post-translational modification can perturb the folding mechanism.

SUBMITTER: Leonard C

PROVIDER: S-EPMC8017153 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Alzheimer's disease is characterized by amyloid-β aggregation. Currently, all the approved medications are to treat the symptoms but there is no clinically approved treatment for the cure or to prevent the progression of Alzheimer's disease (AD). Earlier reports suggest the use of small molecules and peptides to target and destabilize the amyloid fibril. The use of Beta Sheet Breaker (BSB) peptides seems to be a promising and attractive therapeutic approach as it can strongly bind and destabilize the preformed amyloid fibril. There are experimental studies describing the destabilization role of various BSB peptides, but the exact mechanism remains elusive. In the current work, an attempt is made to study the destabilization mechanism of different BSB peptides on preformed amyloid protofibril using molecular docking and simulations. Molecular docking of eight different BSB peptides of varying length (5-mer to 10-mer) on the Abeta protofibril was done. Docking was followed by multiple sets of molecular simulations for the Abeta protofibril-BSB peptide complex for each of the top ranked poses of the eight BSB peptides. As a control, multiple sets of simulations for the Abeta protofibril (APO) were also carried out. An increase in the RMSD, decrease in the number of interchain hydrogen bonds, destabilization of important salt bridge interactions (D23-K28), and destabilization of interchain hydrophobic interactions suggested the destabilization of Abeta protofibril by BSB peptides. The MM-GBSA free energy of binding for each of the BSB peptides was calculated to measure the binding affinity of BSB peptides to Abeta protofibril. Further residue wise contribution of free energy of binding was also calculated. The study showed that 7-mer peptides tend to bind strongly to Abeta protofibril as compared to other BSB peptides. The KKLVFFA peptide showed better destabilization potential as compared to the other BSB peptides. The details about the destabilization mechanism of BSB peptides will help in the design of other peptides for the therapeutic intervention for AD.

Project description:Short peptide sequences within the microtubule binding domain of the protein Tau are proposed to be core nucleation sites for formation of amyloid fibrils displaying the paired helical filament (PHF) morphology characteristic of neurofibrillary tangles. To study the structure of these proposed nucleation sites, we analyzed the x-ray diffraction patterns from the assemblies formed by a variety of PHF/tau-related peptide constructs containing the motifs VQIINK (PHF6*) in the second repeat and VQIVYK (PHF6) in the third repeat of tau. Peptides included: tripeptide acetyl-VYK-amide (AcVYK), tetrapeptide acetyl-IVYK-amide (AcPHF4), hexapeptide acetyl-VQIVYK-amide (AcPHF6), and acetyl-GKVQIINKLDLSNVQKDNIKHGSVQIVYKPVDLSKVT-amide (AcTR4). All diffraction patterns showed reflections at spacings of 4.7 A, 3.8 A, and approximately 8-10 A, which are characteristic of an orthogonal unit cell of beta-sheets having dimensions a=9.4 A, b=6.6 A, and c=approximately 8-10 A (where a, b, and c are the lattice constants in the H-bonding, chain, and intersheet directions). The sharp 4.7 A reflections indicate that the beta-crystallites are likely to be elongated along the H-bonding direction and in a cross-beta conformation. The assembly of the AcTR4 peptide, which contains both the PHF6 and PHF6* motifs, consisted of twisted sheets, as indicated by a unique fanning of the diffuse equatorial scattering and meridional accentuation of the (210) reflection at 3.8 A spacing. The diffraction data for AcVYK, AcPHF4, and AcPHF6 all were consistent with approximately 50 A-wide tubular assemblies having double-walls, where beta-strands constitute the walls. In this structure, the peptides are H-bonded together in the fiber direction, and the intersheet direction is radial. The positive-charged lysine residues face the aqueous medium, and tyrosine-tyrosine aromatic interactions stabilize the intersheet (double-wall) layers. This particular contact, which may be involved in PHF fibril formation, is proposed here as a possible aromatic target for anti-tauopathy drugs.

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Insight Into Seeded Tau Fibril Growth From Molecular Dynamics Simulation of the Alzheimer's Disease Protofibril Core.

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