Molecular modeling of the amyloid-β-peptide using the homology to a fragment of triosephosphate isomerase that forms amyloid in vitro

Carlos F. Contreras, Mauricio A. Canales, Alejandra Alvarez, Giancarlo V. De Ferrari, Nibaldo C. Inestrosa

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)


The main component of the amyloid senile plaques found in Alzheimer's brain is the amyloid-β-peptide (Aβ), a proteolytic product of a membrane precursor protein. Previous structural studies have found different conformations for the Aβ peptide depending on the solvent and pH used. In general, they have suggested an a-helix conformation at the N-terminal domain and a β-sheet conformation for the C-terminal domain. The structure of the complete Aβ peptide (residues 1-40) solved by NMR has revealed that only helical structure is present in Aβ. However, this result cannot explain the large β-sheet Aβ aggregates known to form amyloid under physiological conditions. Therefore, rye investigated the structure of Aβ by molecular modeling based on extensive homology using the Smith and Waterman algorithm implemented in the MPsrch program (Blitz server). The results showed a mean value of 23% identity with selected sequences. Since these values do not allow a clear homology to be established with a reference structure in order to perform molecular modeling studies, we searched for detailed homology. A 28% identical with an α/β segment of a triosephosphate isomerase (TIM) from Culex tarralis with an unsolved three-dimensional structure was obtained. Then, multiple sequence alignment was performed considering Aβ, TIM from C. tarralis and another five TIM sequences with known three-dimensional structures. We found a TIM segment with secondary structure elements in agreement with previous experimental data for Aβ. Moreover when a synthetic peptide from this TIM segment was studied in vitro, it was able to aggregate and to form amyloid fibrils, as established by Congo red binding and electron microscopy. The Aβ model obtained was optimized by molecular dynamics considering ionizable side chains in order to simulate Aβ in a neutral pH environment. We report here the structural implications of this study.

Original languageEnglish
Pages (from-to)959-966
Number of pages8
JournalProtein Engineering
Issue number11
Publication statusPublished - 1999


  • Alzheimer's disease
  • Amyloid
  • Modeling
  • Triosephosphate isomerase

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology


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