Figure 3. Hexamer concentric β-barrel model. (a & b) Flattened representation of four subunits viewed from the exterior as if the barrel were split open on the back side and spread flat. The axes of 2-fold perpendicular symmetry are indicated by green and purple circles behind the β-sheets, and the plane containing these axes by the horizontal line. The arrows represent β-strands colored by segment. The circles represent side chains; those oriented outwardly are larger than those oriented inwardly. They are colored by residue type: white = positively charged (blue letter), negatively charged (red letter), or uncharged polar (black letter), green = ambivalent Gly, light gray = ambivalent His (blue letter) or Thr (black letter), dark gray - white letter = slightly hydrophobic Ala, black - white letter = hydrophobic. The N- and C-termini residues have blue and red outlines to indicate their positive and negative charges. (a) Outer β-barrel; S1a (pink), S1b (orange), and S2 (yellow); parameters are N = 18, S/N = 1.0, D = 3.4 nm. (b) Inner S3 β-barrel; N = 6, S/N = 1.0, D = 1.1 nm. (c) Wedge representation cross-section on the plane containing axes of 2-fold symmetry illustrating relative positions of the β-strands. (d-g) Atomic-scale model. The backbone is illustrated as a rainbow-colored ribbon from red (N-termini) to blue (C-termini). (d) View down the radial axis of the β-barrels. (e) Side view along the 2-fold axis between the yellow S2 strands. (f) Radial cross-section through the central portion with side chains colored by element; hydrogens and carbons are white and gray, polar oxygen and nitrogen atoms are red and blue. Rectangles enclose exposed V18 and F20 side chains. (g) Ribbon representations of six hexamers forming a beaded APF; the insert in the upper right corner is an averaged EM image from Fig. 2.
The exterior surface of the hexamer model has three hydrophobic patches formed by V18 and F20 (rectangles of Fig. 3f) flanked by positively charged K18 and negatively charged E22. These are the most probable interaction regions between APFs in an aqueous solution due to a combination of hydrophobic and electrostatic interactions. Such interactions should be geometrically optimal for hexamers in a bAPF formed from six small beads due to the 2-fold symmetry of the interaction sites (Fig. 3g). In the beaded APF micrograph analyzed here, six-membered APFs dominated the smallest bead APFs; 13 six-membered rings were observed whereas the average number of other small bead bAPFs was only about two (Fig. 2).
Experimental studies indicate that Aβ42 can form dodecamers48,49 and octadecamers50,51, and that these sizes of oligomers can be isolated from brains of Alzheimer’s patients. Some of these may form when additional monomers bind to hexamers. If so, the S3 strands of the additional Aβ monomers will likely bind in a hydrophobic environment. Site-Directed spin-labeling studies indicate that mobility decreases and rigidity increases within Aβ oligomers from the N-terminus to the C-terminus, and that S3 segments are tightly packed52. S1s comprise the most polar, most dynamic, and least conserved of the segments; so much so that in most experimentally-determined structures they are classified as disordered. We hypothesize that S1 segments can be displaced as S2 and/or S3 segments of six additional monomers bind next to S3s and between S2s of the original hexamer (Figs. 4 & 5). The displaced S1a-S1b β-hairpins of the original hexamer may combine with S1a-S1b β-hairpins of the additional monomers to form an outer 24-stranded antiparallel β-barrel with approximate 6-fold radial symmetry (Fig 4), but the outermost barrel or layer is likely to be highly dynamic and difficult to predict precisely.