Concentric β-barrel Models
The general monomer backbone folding motifs used in most of our concentric β-barrel models of synucleins are illustrated in Fig. 6. These were designed so that most of the repeating segments have similar backbone conformations. The initial, relatively hydrophobic portions of the Nt segments form β-strands, and the more polar signature sequences at the ends connect these strands. Sy7 forms a β-hairpin in most cases and its two halves are often extensions of the S6 and/or S8 β-strands.
In most of our Type A models, the Nt domain forms a five-stranded antiparallel β-sheet; these assemble into an antiparallel β-barrel that usually surrounds a central hydrophobic core antiparallel barrel formed by the NAC domains (Fig. 6a). In Type P models Nt segments form portions of two parallel (except where subunits interact in Type 2 models) β-barrels with Sy2 and Sy4 in an inner barrel, and Sy1, Sy3, and Sy5 in the surrounding barrel (Fig.6 b,c,e). Except for small differences in strand tilt and curvature, the Nt domain folding motif is the same for all Type P models that follow. Sequentially adjacent strands are located in different β-barrels and connected by the most highly conserved and charged segments among the repeats, the signature linkers. Locations of NAC strands vary among the models.
Interacting side-chains of sequentially Type P adjacent strands may fit between one another (Fig. 6e) in a manner similar, but not identical, to steric zippers [56]. The major differences are that the interaction between side-chains of adjacent β-barrels is not one-to-one and the differences in tilts of the strands can affect side-chain packing. The pitch of a β-barrel’s pleats as they spiral around the barrel can be approximated by P = C tan α where P is the pitch, C is the circumference of the barrel, and α is the tilt angle of the strand determined by the S/N ratio, where S is the sheer number of the barrel and N is its number of strands. When P is about the same for adjacent concentric barrels, the pleats can fit between each other similar to the threads of a bolt fitting into a nut (Fig. 6d); we refer to this situation as intermeshing pleats. This is more probable when α of the surrounding barrel is less than that of the more interior barrel. In Type 2 models some pleats intersect an axis of 2-fold-perpendicular symmetry present in all the barrels. For the pleats of concentric barrels to intermesh at these points the pleats of all concentric barrels must have the same orientation (inward or outward) at these regions. This criteria places additional constraints on S/N values of the concentric barrels. The small size of the putative interacting side-chains in the Syn models likely facilitates tight packing between the barrels and reduces steric clashes among side-chains, especially when P values of adjacent β-barrels differ substantially.