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

The main component of the amyloid senile plaques found in Alzheimer's brain is the amyloid-beta-peptide (A beta), a proteolytic product of a membrane precursor protein. Previous structural studies have found different conform ations for the A beta peptide depending on the solvent and pH used. In gene ral, they have suggested an alpha-helix conformation at the N-terminal doma in and a beta-sheet conformation for the C-terminal domain. The structure o f the complete A beta peptide (residues 1-40) solved by NMR has revealed th at only helical structure is present in A beta. However, this result cannot explain the large beta-sheet A beta aggregates known to form amyloid under physiological conditions. Therefore, we investigated the structure of A be ta by molecular modeling based on extensive homology using the Smith and Wa terman algorithm implemented in the MPsrch program (Blitz server). The resu lts showed a mean value of 23 % identity with selected sequences. Since the se values do not allow a clear homology to be established with a reference structure in order to perform molecular modeling studies, we searched for d etailed homology, A 28% identity with an alpha/beta segment of a triosephos phate isomerase (TIM) from Culex tarralis with an unsolved three-dimensiona l structure was obtained. Then, multiple sequence alignment was performed c onsidering A beta, TIM from C.tarralis and another five TIM sequences with known three-dimensional structures. We found a TIM segment with secondary s tructure elements in agreement with previous experimental data for A beta. Moreover, when a synthetic peptide from this TIM segment was studied in vit ro, it was able to aggregate and to form amyloid fibrils, as established by Congo red binding and electron microscopy, The A beta model obtained was o ptimized by molecular dynamics considering ionizable side chains in order t o simulate A beta in a neutral pH environment. We report here the structura l implications of this study.