Globular state in the oligomers formed by Abeta peptides

Abstract

Replica exchange molecular dynamics and implicit solvent model are used to study two oligomeric species of Abeta peptides, dimer and tetramer, which are typically observed in in vitro experiments. Based on the analysis of free energy landscapes, density distributions, and chain flexibility, we propose that the oligomer formation is a continuous transition occurring without metastable states. The density distribution computations suggest that Abeta oligomer consists of two volume regions-the core with fairly flat density profile and the surface layer with rapidly decreasing density. The core is mostly formed by the N-terminal residues, whereas the C-terminal tends to occur in the surface layer. Lowering the temperature results in the redistribution of peptide atoms from the surface layer into the core. Using these findings, we argue that Abeta oligomer resembles polymer globule in poor solvent. Abeta dimers and tetramers are found to be structurally similar suggesting that the conformations of Abeta peptides do not depend on the order of small oligomers.

Figure 1

(a) The sequence of Aβ_10–40 peptide and the allocation of the N-terminal Nt and C-terminal Ct regions. [(b) and (c)] Typical structures of Aβ oligomers, tetramer (b) and dimer (c), sampled at 360 K. The N- and C-terminals are colored in shades of red and yellow, respectively. The Aβ Nt region tends to form the oligomer’s core, whereas the Ct mostly makes up the surface layer. The structures are visualized using Chimera (Ref. 60).

Figure 2

(a) Free energies of Aβ_10–40 peptide F(C_h) as a function of the number of interpeptide hydrophobic side chain contacts C_h at 360 K. The free energy of peptide incorporation into the oligomer is ΔF_O-D=F_O−F_D, where F_O and F_D=0 are the free energies of the associated (O) and dissociated (D,C_h=0) states. F_O is obtained by integrating over the O states (shaded in gray) for which F(C_h)≤F_min+1.0RT, where F_min is the minimum in F(C_h). (b) Temperature dependence of the oligomer free energy F(T). Quadratic fitting functions F(T)≃−α(T−T_o)² are shown by black continuous curves. The fitting parameters are α=−0.003 kcal∕(mol K²),T_o=371 K (dimer) and α=−0.007 kcal∕(mol K²), T_o=382 K (tetramer). Maximum values of F(T) are set to zero. In panels (a) and (b) the data for dimer and tetramer are shown by open and filled circles, respectively. The figure suggests that the formation of oligomer is a continuous transition without intermediate states.

Figure 3

(a) Normalized radial distribution function for the number density g(r) in the Aβ tetramer (thick line) and dimer (thin line) at 360 K. The distance r is measured with respect to the center of mass of the oligomer. The profiles of g(r) suggest that the oligomer volume can be divided into two regions—the core (r<R_c) and the surface layer (R_c<r<R_s). (b) Normalized radial distributions g(r) for the tetramer computed in the temperature range from 330 to 490 K with 5 K increment. The plots implicate the expansion of the oligomer with the increase in temperature. Inset: Temperature dependences of the core radius R_c (in black) and the thickness of surface layer ΔR (in gray): tetramer (filled circles) and dimer (open circles). Monotonic increase in ΔR with temperature coupled with relatively constant R_c suggests that the oligomer expansion is due to the swelling of the surface layer. In (a) and (b) dotted lines mark the minimum density levels in the core (0.7g(0)) and in the surface layer (0.3g(0)).

Figure 4

The temperature dependence of the core number density n_c(T) in Aβ oligomer. The plot shows that the atom packing in the core increases at low temperatures. Inset: the fraction of oligomer atoms in the core, Φ_c(T), as a function of temperature. The temperature, at which half of Aβ atoms are confined to the core, approximately coincides with the temperature of oligomer formation T_o [Fig. 2b]. Dotted line marks the level Φ_c=0.5. Data for the dimer and tetramer are shown by open and filled circles, respectively.

Figure 5

(a) The distribution of relative solvent accessible surface areas of amino acids i, ⟨rASA(i)⟩, in Aβ peptide. (b) Probabilities of occurrence of the residues i in the oligomer core, P_c(i). Data for the dimer and tetramer are shown by open and filled circles, respectively. Inset: standard deviations in the backbone dihedral angles ϕ(i), δϕ(i) (black bars), and ψ(i), δψ(i) (gray bars) in the tetramer as a function of the amino acid index i. The figure shows that the N-terminal Nt is mostly buried in the oligomer core, whereas the C-terminal Ct forms the surface layer. The Nt and Ct amino acids in Aβ peptide are boxed. The plots are computed at 360 K.