Thermodynamics and dynamics of amyloid peptide oligomerization are sequence dependent

Abstract

Aggregation of the full‐length amyloid‐β (Aβ) and β2‐microglobulin (β2m) 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 β2m83‐89 NHVTLSQ and Aβ16‐22 KLVFFAE fragments. Based on multiple trajectories run at 310 K, totaling 2.2 μs (β2m83‐89) and 4.8 μs (Aβ16‐22) 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 Aβ16‐22 with respect to β2m83‐89 impacts the thermodynamics by reducing the population of bilayer β‐sheet assemblies. Higher hydrophobicity is also found to slow down the dynamics of β‐sheet formation by enhancing the averaged lifetime of all configuration types (CT) and by reducing the complexity of the CT transition probability matrix. Proteins 2009. © 2008 Wiley‐Liss, Inc.

Effect of the Tottori Familial Disease Mutation (D7N) on the Monomers and Dimers of Aβ40and Aβ42

“…While an increased β-strand from Aβ 42 -WT monomer (21%) to Aβ 40 -WT monomer (6%) correlates with the observation that Aβ 42 forms fibrils faster than Aβ 40 , a reduction of β-strand content from Aβ 42 -WT dimer (24%) to Aβ 40 -WT dimer (32%), a constant β-strand content for Aβ 40 dimer upon D7N mutation and a 50% reduction of β-strand content in Aβ 42 dimer upon D7N mutation do not contradict the basic understanding of the differences between the two alloforms. Indeed, it is well established that other physicochemical factors such as charge and hydrophobicity contribute to enhanced aggregation rates, 61 and what counts in explaining aggregation rate variation is not a Shown are the population P (in %), the mean values of the total fibril contacts (N fb ), the center of mass distance (in nm) between the 7th residues of two chains (d R7 ), the secondary structure contents (in %) using residues 1−40, the populations (in %) of intramolecular two-stranded β-sheet (iP bs 2s ), intermolecular two-stranded β-sheet (oP bs 2s ), three-stranded β-sheet (P bs 3s ), and four-stranded β-sheet (P bs 4s ). The populations of higher-stranded β-sheets are almost zero.…”

Driving Forces and Structural Determinants of Steric Zipper Peptide Oligomer Formation Elucidated by Atomistic Simulations

“…The properties of small multimeric aggregates (dimers to decamers) of various amyloidogenic peptide sequences have been studied by atomistic simulations and described as partially ordered, nematic structures, which are subject to rapid fluctuations and large conformational rearrangements. 41,42,[48][49][50][51][52][53][54][55][56] The obtained oligomer ensembles are described as distinct from the monomeric form 48,52,57 due to the conformational changes associated with emerging β-sheet structure. 49,56 These structural transitions were found to be accompanied by a loss of intra-peptide interactions and conformational entropy.…”

Globular state in the oligomers formed by Aβ peptides

“…25,26 MD investigations of A␤ oligomers, which are more computationally intensive, have been recently reported. [33][34][35][36][37] In general, these studies have shown that aggregation leads to considerable conformational changes in A␤ peptides. For example, we have found that interpeptide interactions in A␤ dimers induce a profound shift in the secondary structure, resulting in the conversion of helical states into ␤-strand conformations.…”