Computationally derived structural models of the beta-amyloid found in Alzheimer's disease plaques and the interaction with possible aggregation inhibitors.

We report the modeling of and possible interactions within the solid beta-amyloid (ABeta) 1-43 fibril, the most fibrillogenic peptide known. All models proposed are consistent with the known experimental structural data, in terms of both secondary structure and packing motifs. The model containing antiparallel beta-sheets, and a beta-turn at G(25)S(26)N(27)K(28) has the lowest calculated packing energy. As such, it can be considered a reasonable model for solid beta-amyloid in Alzheimer's disease plaques. Interestingly, with the turn located at this position, the 1-43 structure is stabilized by a number of complementary intermolecular interactions between the beta-sheets. These well-defined interactions exist for the side-chain residues of 41, 42, and 43 with adjacent ABeta molecules. These interactions would not be conserved in the 1-40 peptide, and indeed, this enhanced interaction is proposed to give rise to the increased fibrillogenic nature of the ABeta 1-43 species over the 1-40 form. The models are used to explain the increased fibrillogenic nature of the Dutch family mutation of ABeta. These models are also employed to examine possible docking interactions of previously reported antiaggregation inhibitors, such as 4'-deoxy-4'-iododoxorubicin (IDOX) onto the theoretical growing surface. A docked structure of IDOX with the model of the solid fibril is described and a proposal for the mechanism of its antiaggregation properties is presented. Copyright 1999 John Wiley & Sons, Inc.