Influence of preformed Asp23-Lys28 salt bridge on the conformational fluctuations of monomers and dimers of Aβ peptides with implications for rates of fibril formation

摘要

Recent experiments have shown that the congener, Aβ1–40[D23-K28], in which the side chains of charged residues Asp23 and Lys28 are linked by a lactam bridge, forms amyloid fibrils that are structurally similar to the wild type (WT) Aβ peptide, but at a rate that is nearly thousand times faster. We used all atom molecular dynamics in explicit water, and two force fields, of the WT dimer, a monomer with the lactam bridge (Aβ10–35-lactam[D23-K28]), the monomer and dimers with harmonically constrained D23-K28 salt bridge (Aβ10–35[D23-K28]), to understand the origin of the enhanced fibril rate formation. The simulations show that the assembly-competent fibril like monomer (N*) structure, that is present among the conformations sampled by the isolated monomer, with strand conformations in the residues spanning the N and C termini and a bend involving residues D²³VGSNKG²⁹, are populated to a much greater extent in Aβ10–35[D23-K28] and Aβ10–35-lactam[D23-K28] than in the WT, which has negligible probability of forming N*. The salt bridge in N* of Aβ10–35[D23-K28], whose topology is similar to that found in the fibril, is hydrated. The reduction in the free energy barrier to fibril formation in Aβ10–35[D23-K28] and in Aβ10–35-lactam[D23-K28], compared to the WT, arises largely due to entropic restriction that enables the bend formation. A decrease in the entropy of the unfolded state and the lesser penalty for conformational rearrangement including the formation of the salt bridge in Aβ peptides with D23-K28 constraint results in a reduction in the kinetic barrier in the Aβ1–40-lactam[D23-K28] congener compared to the WT. The decrease in the barrier, that is related to the free energy cost of forming a bend, is estimated to be in the range (4–7)kBT. Although a number of factors determine the growth of fibrils, the decrease in the free energy barrier, relative to the WT, to N* formation is a major factor in the rate enhancement in the fibril formation of Aβ1–40[D23-K28] congener. Qualitatively similar results were obtained using simulations of Aβ9–40 peptides, and various constructs related to the Aβ10–35 systems that were probed using OPLS and CHARMM force fields. We hypothesize that mutations or other constraints that preferentially enhance the population of N* species would speed up aggregation rates. Conversely, ligands that lock it in the fibril-like N* structure would prevent amyloid formation.