Morphology of a Transmembrane A₄₂ Tetramer via REMD Simulations

The folding/misfolding of membrane-permiable Amyloidbeta (A & beta;)peptides is likely associated with the advancing stage of Alzheimer'sdisease (AD) by disrupting Ca2+ homeostasis. In this context,the aggregation of four transmembrane A & beta;(17-42) peptides was investigated using temperature replica-exchange moleculardynamics (REMD) simulations. The obtained results indicated that thesecondary structure of transmembrane A & beta; peptides tends to havedifferent propensities compared to those in solution. Interestingly,the residues favorably forming & beta;-structure were interleavedby residues rigidly adopting turn-structure. A combination of & beta;and turn regions likely forms a pore structure. Six morphologies of4A & beta; were found over the free energy landscape and clusteringanalyses. Among these, the morphologies include (1) A & beta; bindingonto the membrane surface and three transmembrane A & beta;; (2) threehelical and coil transmembrane A & beta;; (3) four helical transmembraneA & beta;; (4) three helical and one & beta;-hairpin transmembraneA & beta;; (5) two helical and two & beta;-strand transmembrane A & beta;;and (6) three & beta;-strand and one helical transmembrane A & beta;.Although the formation of the & beta;-barrel structure was not observedduring the 0.28 ms Rlong MD simulation, the structure is likelyto form when the simulation time is further extended.