Structural properties of amyloid beta(1-40) dimer explored by replica exchange molecular dynamics simulations

摘要

Replica exchange molecular dynamics simulations (300 ns) were used to study the dimerization of amyloid beta(1-40) (A beta(1-40)) polypeptide. Configurational entropy calculations revealed that at physiological temperature (310 K, 37 degrees C) dynamic dimers are formed by randomly docked monomers. Free energy of binding of the two chains to each other was -93.56 +/- 6.341 kJ mol(-1). Prevalence of random coil conformations was found for both chains with the exceptions of increased beta-sheet content from residues 16-21 and 29-32 of chain A and residues 15-21 and 30-33 of chain B with beta-turn/beta-bend conformations in both chains from residues 1-16, 21-29 of chain A, 1-16, and 21-29 of chain B. There is a mixed beta-turn/beta-sheet region from residues 33-38 of both chains. Analysis of intra-and interchain residue distances shows that, although the individual chains are highly flexible, the dimer system stays in a loosely packed antiparallel beta-sheet configuration with contacts between residues 17-21 of chain A with residues 17-21 and 31-36 of chain B as well as residues 31-36 of chain A with residues 17-21 and 31-36 of chain B. Based on dihedral principal component analysis, the antiparallel beta-sheet-loop-beta-sheet conformational motif is favored for many low energy sampled conformations. Our results show that A beta(1-40) can form dynamic dimers in aqueous solution that have significant conformational flexibility and are stabilized by collapse of the central and C-terminal hydrophobic cores with the expected beta-sheet-loop-beta-sheet conformational motif. (C) 2017 Wiley Periodicals, Inc.