Figure 4. Dodecamer models. Parameters of the barrel are listed below the octadecamer schematics. The color code for the dodecamer strands and residues is the same as in the previous figures. The structures of the core S2 and S3 strands of the hexamer are maintained as additional subunits (stippled), and the core S1a-S1b hairpins (sides of outer barrel) are displaced outwardly to the third barrel. (a) Wedge representations of the central cross-section; peripheral subunits are stippled. (b-d) Flattened schematics of four subunits of (b) the inner 6-stranded S3 β-barrel (same as hexamer), (c) the middle 18-stranded S2 and S3 β-barrel, and (d) the outer 24-stranded S1a-S1b β-barrel. (e-h) Atomic-scale models of the dodecamer. (e & f) Rainbow colored ribbon illustration of the backbone as viewed from the top and side. (g & h) Cross-sections with side chains colored by element viewed along the barrels’ axis and from the side. Note that most buried side chains are tightly packed and hydrophobic (gray carbons, white hydrogens, and yellow sulfurs), and that most surface side chains have polar red oxygen or blue nitrogen atoms with white hydrogens.
Aβ homologs comprise a large superfamily present in most vertebrates. Multiple studies indicate that they have a functional role38,53,54 including antimicrobial activity55. We aligned 2500 homologous sequences from mammals through bony fish (Supplement Fig. S2). Residues 28 – 42 of the S3 segment are incredibly conserved; the sequences are identical in all but three positions and even those substitutions are limited to large alkyl side chains: i.e., I32-V or L, V39-I, and V40-I (Fig. S2). Only one substitution occurs at V12 in S1b, and at K16, L17, V18, F19, and N27 in S2. Only three or four residue types occur at D1 and E3 in S1a, at Y10 in S1b, and at Q15, F20, A21, D23, and S26 of S2. All hypervariable positions where five or more residue types and deletions occur are in S1 or toward the end of S2. The high degree of conservation in S2 and S3 suggest that these proteins adopt a functional conformation or conformations in which at least some S3 segments and conserved portions of S2 are buried within the protein complex, and in which most of S1a is peripheral and likely disordered. Mutagenesis studies indicate that S3 residues I31, I32, L34, V39, V40 and I42 are key to Aβ oligomerization56. The octadecamer model of Fig. 5 was developed in part based on the hypothesis that all highly conserved hydrophobic residues form a core structure that is buried in this model. S1a is peripheral as are outwardly oriented side chains of S1b. Side chain packing between barrels is quite tight with few large cavities; all conserved hydrophobic side chains (blue and cyan) and most semi-conserved side chains (yellow and green) are buried, the hypervariable side chain positions (red) are peripheral, backbone H-bonding is extensive, and almost all charged groups form salt bridges.