Thermodynamics and dynamics of amyloid peptide oligomerization are sequence dependent

Aggregation of the full-length amyloid-beta (A beta) and beta 2-microglobulin (beta 2m) proteins is associated with Alzheimer's disease and dialysis-related amyloidosis, respectively. This assembly process is not restricted to full-length proteins, however, many short peptides also assemble into amyloid fibrils in vitro. Remarkably, the kinetics of amyloid-fibril formation of all these molecules is generally described by a nucleation-polymerization process characterized by a lag phase associated with the formation of a nucleus, after which fibril elongation occurs rapidly. In this study, we report using long molecular dynamics simulations with the OPEP coarse-grained force field, the thermodynamics and dynamics of the octamerization for two amyloid 7-residue peptides: the beta 2m83-89 NHVTLSQ and A beta 16-22 KLVFFAE fragments. Based on multiple trajectories run at 310 K, totaling 2.2 mu s (beta 2m83-89) and 4.8 mu s (A beta 16-22) and starting from random configurations and orientations of the chains, we find that the two peptides not only share common but also very different aggregation properties. Notably, an increase in the hydrophobic character of the peptide, as observed in A beta 16-22 with respect to beta 2m83-89 impacts the thermodynamics by reducing the population of bilayer beta-sheet assemblies. Higher hydrophobicity is also found to slow down the dynamics of beta-sheet formation by enhancing the averaged lifetime of all configuration types (CT) and by reducing the complexity of the CT transition probability matrix.