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Protein Engineering, Vol. 12, No. 11, 959-966, November 1999
© 1999 Oxford University Press

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

Carlos F. Contreras, Mauricio A. Canales, Alejandra Alvarez1, Giancarlo V. de Ferrari1 and Nibaldo C. Inestrosa1,2

Laboratorio de Biofísica Molecular, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción and 1 Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, PO Box 114-D, Alameda 340, Santiago, Chile

The main component of the amyloid senile plaques found in Alzheimer's brain is the amyloid-ß-peptide (Aß), a proteolytic product of a membrane precursor protein. Previous structural studies have found different conformations for the Aß peptide depending on the solvent and pH used. In general, they have suggested an {alpha}-helix conformation at the N-terminal domain and a ß-sheet conformation for the C-terminal domain. The structure of the complete Aß peptide (residues 1–40) solved by NMR has revealed that only helical structure is present in Aß. However, this result cannot explain the large ß-sheet Aß aggregates known to form amyloid under physiological conditions. Therefore, we investigated the structure of Aß 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% identity with an {alpha}/ß segment of a triosephosphate isomerase (TIM) from Culex tarralis with an unsolved three-dimensional structure was obtained. Then, multiple sequence alignment was performed considering Aß, 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 Aß. 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 Aß model obtained was optimized by molecular dynamics considering ionizable side chains in order to simulate Aß in a neutral pH environment. We report here the structural implications of this study.

Keywords: Alzheimer's disease/amyloid/modeling/triosephosphate isomerase

2 To whom correspondence should be addressed


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