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.