Principles governing oligomer formation in amyloidogenic peptides

Abstract

Identifying the principles that describe the formation of protein oligomers and fibrils with distinct morphologies is a daunting problem. Here we summarize general principles of oligomer formation gleaned from molecular dynamics simulations of Abeta-peptides. The spectra of high free energy structures sampled by the monomer provide insights into the plausible fibril structures, providing a rationale for the 'strain phenomenon.' Heterogeneous growth dynamics of small oligomers of Abeta(16-22), whose lowest free energy structures are like nematic droplets, can be broadly described using a two-stage dock-lock mechanism. In the growth process, water is found to play various roles depending on the oligomer size, and peptide length, and sequence. Water may be an explicit element of fibril structure linked to various fibril morphologies.

Figure 1

Free energy spectrum of Aβ_10–35 monomer obtained from MD simulations. States with the disrupted salt bridge are more favorable, and a large barrier makes the transition between the formed and disrupted substates improbable. Burying K28 in the peptide interior is an unfavorable process. The number of microstates associated with each of the four basins is indicated in parentheses. D23-K28 on stands for salt bridge present, while D23-K28 off stands for salt bridge broken. Reprinted from [21].

Figure 2

Free energy landscape of Aβ_1–40 and the Aβ_1–40 [D23-K28] peptide congener. By constraining the D23 and K28 residues to be proximate, through a theoretical constraint or formation of a covalent β-lactam bond, the free energy barrier between the monomer and the aggregation competent N^* is reduced. Reprinted from [38].

Figure 3

Structure of the hydrated monomer in Aβ_1–40 fibril. The blue shade represents trapped water molecules that are localized in a hydrophobic pocket. Reprinted from [68].