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-a myloid (ABeta) 1-43 fibril, the most fibrillogenic peptide known. All model s proposed are consistent with the known experimental structural data, in t erms of both secondary structure and packing motifs. The model containing a ntiparallel beta-sheets, and a beta-turn at G(25)S(26)N(27)K(28) has the lo west calculated packing energy. As such, it can be considered a reasonable model for solid P-amyloid in Alzheimer's disease plaques. Interestingly wit h 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 c onserved in the 1-40 peptide, and indeed, this enhanced interaction is prop osed to give rise to the increased fibrillogenic nature of the ABeta 1-43 s pecies over the 1-40 form. The models are used to explain the increased fib rillogenic nature of the Dutch family mutation of ABeta. These models are a lso employed to examine possible docking interactions of previously reporte d antiaggregation inhibitors, such as 4'-deoxy-4'-iododoxorubicin (IDOX) on to the theoretical growing surface. A docked structure of IDOX with the mod el of the solid fibril is described and a proposal for the mechanism of its antiaggregation properties is presented. (C) 1999 John Wiley & Sons, Inc.