Mechanistic insight into E22Q-mutation-induced antiparallel-to-parallel β-sheet transition of Aβ16-22 fibrils: an all-atom simulation study

Alzheimer's disease is associated with the abnormal self-assembly of amyloid-beta (A beta) peptide into toxic oligomers and fibrils. Recent experiments reported that A beta(16-22), containing the central hydrophobic core (CHC) of A beta, formed antiparallel beta-sheet fibrils, while its E22Q mutant self-assembled into parallel beta-sheet fibrils. However, the molecular mechanisms underlying E22Q-mutation-induced parallel beta-sheet fibril formation are not well understood. Herein, we performed molecular dynamics (MD) simulations to study the dimerization processes of A beta(16-22) and A beta(16-22)E22Q peptides. beta-Sheet dimers with diverse hydrogen bond arrangements were observed and they exhibited highly dynamic and interconverting properties. An antiparallel-to-parallel beta-sheet transition occurred in the assembly process of the E22Q mutant, but not in that of A beta(16-22). During this conformational transformation process, the inter-molecular Q22-Q22 hydrogen bonds were first formed and acted as a binder to facilitate the two chains forming a parallel orientation, then the hydrophobic interactions between residues in the CHC region consolidated this arrangement and drove the main-chain H-bond formation, hence resulting in parallel beta-sheet formation. However, parallel beta-sheets were less populated than antiparallel beta-sheets of A beta(16-22)E22Q dimers. In order to explore whether parallel beta-sheets became dominant in larger size oligomers, we investigated the conformational ensembles of A beta(16-22) and A beta(16-22)E22Q octamers by conducting replica exchange molecular dynamics (REMD) simulations. The REMD simulations revealed that the population of parallel beta-strand alignment increased with an increase of the size of ordered A beta(16-22)E22Q beta-sheet oligomers, implying that the formation of full parallel beta-sheets requires larger sized oligomers. Our findings provide a mechanistic explanation for the E22Q-mutation-induced formation of parallel beta-sheet fibrils observed experimentally.