Abstract: The region encompassing residues 13–23 of the amyloid beta peptide (A(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 A(13–23) and been computationally shown to do so with high affinity. More interactions are available in full-length A 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, A(1–42). The relative stabilities of the A–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 A(1–42) in an antiparallel -sheet fashion. Another complex, designated AB3, also involved SGA1 binding to the self-recognition region of A(1–42), albeit with lower affinity. In both AB1 and AB3, SGA1 formed antiparallel -sheets but to opposite edges of A. A complex, AB4, with similar stability to AB3, was found with a parallel -sheet in the self-recognition site. A fourth complex, AB7, also with similar stability, formed a parallel -sheet in the hydrophobic central region of A. In all cases, complexation of SGA1 induced extensive -sheet structure in A(1–42).
