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 Aβ_(1-40)[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 1000 times faster. We used all atom molecular dynamics simulations in explicit water, and two force fields, of the WT dimer, a monomer with the lactam bridge (Aβ_(10-35)-lactam[D23—K28]), and the monomer and dimers with harmonically constrained D23—K28 salt bridge (Aβ_(10-35)[D23—K28]) to understand the origin of the enhanced fibril rate formation. The simulations show that the assembly competent fibril-like monomer (N~*) structure, which 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 D~(23) VGSNKG~(29), are populated to a much greater extent in Aβ_(10-35)[D23—K28] and Aβ_(10-35)-lactam[D23—K28] than in the WT, which has negligible probability of forming N~*. The salt bridge in N~* of Aβ_(10-35)[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 Aβ_(10-35)[D23—K28] and in Aβ_(10-35)-lactam[D23—K28], compared to the WT, arises largely due to entropic restriction which 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 Aβ_(1-40)-lactam[D23—K28] congener compared to the WT. The decrease in the barrier, which is related to the free energy cost of forming a bend, is estimated to be in the range (4—7)k_BT. 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 Aβ_(1-40)[D23—K28] congener. Qualitatively similar results were obtained using simulations of Aβ_(1-40) peptides and various constructs related to the Aβ_(10-35) systems that were probed using OPLS and CHARMM force fields. We hypothesize that mutations or other constraints that preferentially enhance the population of the N~* species would speed up aggregation rates. Conversely, ligands that lock it in the fibril-like N~* structure would prevent amyloid formation.