Pathway Complexity of Alzheimer's β-Amyloid Aβ16-22 Peptide Assembly

Abstract

Recent studies suggest that both soluble oligomers and insoluble fibrils have toxic effects in cell cultures, raising the interest in determining the first steps of the assembly process. We have determined the aggregation mechanisms of Abeta(16-22) dimer using the activation-relaxation technique and an approximate free energy model. Consistent with the NMR solid-state analysis, the dimer is predicted to prefer an antiparallel beta sheet structure with the expected registry of intermolecular hydrogen bonds. The simulations, however, locate three other antiparallel minima with nonnative beta sheet registries and one parallel beta sheet structure, slightly destabilized with respect to the ground state. This result is significant because it can explain the observed dependency of beta sheet registry on pH conditions. We also find that assembly of Abeta(16-22) into dimers follows multiple routes, but alpha-helical intermediates are not obligatory. This indicates that destabilization of alpha-helical intermediates is unlikely to abolish oligomerization of Abeta peptides.

Computer Simulations of Alzheimers Amyloid β-Protein Folding and Assembly

“…Using the ART and an approximate free energy model, Santini et al showed that an in-register antiparallel -sheet structure was the most stable structure for the A (16)(17)(18)(19)(20)(21)(22) dimer, despite the existence of several hydrogen bond patterns in both parallel and antiparallel orientations that were thermodynamically possible [110,111]. The existence of alternative -sheet organizations is important because it helps explain the dependence of -sheet registry on pH [105] and amino acid composition [112].…”

ARTIST: An activated method in internal coordinate space for sampling protein energy landscapes

“…14,15 In its current implementation (ART nouveau), 15 the method was also adapted to systems having high and low-frequency vibrational modes 17 and was used to study the folding pathways of a ␤-hairpin peptide model as well as multimers of amyloid-forming peptides. 18,31,32 In all cases, ART in Cartesian coordinate space succeeded in identifying folding mechanisms considerably more complex than those previously proposed. As an example, ART combined with a simplified generic force field (OPEP [33][34] ) revealed that the rate-limiting in the assembly of three peptide chains into a cross-␤ structure involves the reptation of one strand over another.…”

“…This is an important problem because there is both experimental and theoretical evidence that multidomain proteins are not rigidly packed, but are rather dynamic structures. 42,43 For these initial tests, we use a helical-hairpin model derived from the PDB entry 1ABZ 44 and consisting of two ␣-helices (residues 6 -16 and 22-33) connected by a loop (residues [17][18][19][20][21]. This system contains 399 atoms and has 242 internal coordinates.…”

“…nique (ART), which has already been used successfully in Cartesian coordinate studies of protein dynamics. 17,18 This method has been shown to be the most efficient activated algorithm for exploring the energy landscapes of high-dimensional systems. 19 In the following section, we give a general description of the two programs that have been merged to make internal coordinate searches of protein conformations, namely LI-GAND and ART.…”

Rate Kinetics and Molecular Dynamics of the Structural Transitions in Amyloidogenic Proteins

“…Simulation of two short Aβ (16)(17)(18)(19)(20)(21)(22) peptides by Santini et al 18 showed multiple complex routes to fibrillization involving various networks of hydrogen bonds.…”