Specific interactions between amyloid-β peptides in an amyloid-β hexamer with three-fold symmetry: Ab initio fragment molecular orbital calculations in water

Ishimura, Hiromi; Tomioka, Shogo; Kadoya, Ryushi; Shimamura, Kanako; Okamoto, Akisumi; Shulga, Sergiy; Kurita, Noriyuki

doi:10.1016/j.cplett.2017.01.041

Cited by 7 publications

(2 citation statements)

References 35 publications

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“…Alred et al [35] compared the conformational stability of this fibril to that of a two-fold symmetric Aβ fibril. Other studies investigated the fibril growth mechanism by coarse grained MD simulations [36] or the strength of peptide interactions by quantum chemical methods [37]. Thus, although three-fold symmetric Aβ fibrils with structured N-terminus have already been studied by MD simulations, the structural role of the N-terminus has not yet been investigated in detail.…”

Section: Introductionmentioning

confidence: 99%

Role of the N-terminus for the stability of an amyloid-β fibril with three-fold symmetry

2017

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A key player in Alzheimer’s disease is the peptide amyloid-beta (Aβ), whose aggregation into small soluble oligomers, protofilaments, and fibrils finally leads to plaque deposits in human brains. The aggregation behavior of Aβ is strongly modulated by the nature and composition of the peptide’s environment and by its primary sequence properties. The N-terminal residues of Aβ play an important role, because they are known to change the peptide’s aggregation propensity. Since these residues are for the first time completely resolved at the molecular level in a three-fold symmetric fibril structure derived from a patient, we chose that system as template for a systematic investigation of the influence of the N-terminus upon structural stability. Using atomistic molecular dynamics simulations, we examined several fibrillar systems comprising three, six, twelve and an infinite number of layers, both with and without the first eight residues. First, we found that three layers are not sufficient to stabilize the respective Aβ topology. Second, we observed a clear stabilizing effect of the N-terminal residues upon the overall fibril fold: truncated Aβ systems were less stable than their full-length counterparts. The N-terminal residues Arg5, Asp7, and Ser8 were found to form important interfilament contacts stabilizing the overall fibril structure of three-fold symmetry. Finally, similar structural rearrangements of the truncated Aβ species in different simulations prompted us to suggest a potential mechanism involved in the formation of amyloid fibrils with three-fold symmetry.

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Section: Introductionmentioning

confidence: 99%

Role of the N-terminus for the stability of an amyloid-β fibril with three-fold symmetry

2017

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“…The FMO method provides valuable information about the electronic properties of fragments and their molecular interactions. Recently, this method has been extensively used to study A β –ligand binding and stabilizing factors in small A β oligomers 30‐37 …”

Section: Introductionmentioning

confidence: 99%

Identification of key stabilizing interactions of amyloid‐β oligomers based on fragment molecular orbital calculations on macrocyclic β‐hairpin peptides

Firouzi

Noohi

2021

Proteins

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Analyzing the electronic states and inter‐/intra‐molecular interactions of amyloid oligomers expand our understanding of the molecular basis of Alzheimer's disease and other amyloid diseases. In the current study, several high‐resolution crystal structures of oligomeric assemblies of Aβ‐derived peptides have been studied by the ab initio fragment molecular orbital (FMO) method. The FMO method provides comprehensive details of the molecular interactions between the residues of the amyloid oligomers at the quantum mechanical level. Based on the calculations, two sequential aromatic residues (F19 and F20) and negatively charged E22 on the central region of Aβ have been identified as key residues in oligomer stabilization and potential interesting pharmacophores for preventing oligomer formation.

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FMO Interfaced with Molecular Dynamics Simulation

Komeiji¹,

Ishikawa

2021

Recent Advances of the Fragment Molecular Orbital Method

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Specific interactions between amyloid-β peptides in an amyloid-β hexamer with three-fold symmetry: Ab initio fragment molecular orbital calculations in water

Cited by 7 publications

References 35 publications

Role of the N-terminus for the stability of an amyloid-β fibril with three-fold symmetry

Role of the N-terminus for the stability of an amyloid-β fibril with three-fold symmetry

Identification of key stabilizing interactions of amyloid‐β oligomers based on fragment molecular orbital calculations on macrocyclic β‐hairpin peptides

FMO Interfaced with Molecular Dynamics Simulation

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