Molecular dynamics studies of a β-sheet blocking peptide with the full-length amyloid beta peptide of Alzheimer's disease

The region encompassing residues 13-23 of the amyloid beta peptide (Aβ(13-23)) of Alzheimer’s disease is the self-recognition site that initiates toxic oligomerization and fibrillization. A number of pseudopeptides have been designed to bind to Aβ(13-23) and been shown computationally to do so with high affinity. More interactions are available in full length Aβ than are available in the shorter peptide. We describe herein a study by molecular dynamics (MD) of nine distinct complexes formed by one such pseudopeptide, SGA1, with full length beta amyloid, Aβ(1-42). The relative stabilities of the Aβ-SGA1 complexes were estimated by a combination of MD and ab initio methods. The most stable complex, designated AB1, was found to be one in which SGA1 is bound to the self recognition site of Aβ(1-42) in an antiparallel β-sheet fashion. Another complex, designated AB3 also involved SGA1 binding to the self recognition region of Aβ(1-42), albeit with lower affinity. In both AB1 and AB3, SGA1 formed antiparallel β-sheets but to opposite edges of Aβ. A complex, AB4, with similar stability to AB3, was found with a parallel β-sheet in the self recognition site. A fourth complex, AB7, also with similar stability, formed a parallel β-sheet in the hydrophobic central region of Aβ. In all cases, complexation of SGA1 induced extensive β-sheet structure in Aβ(1-42).The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author