De Novo Design of Proteins - Peptide and Protein Design for Biopharmaceutical Applications - page 212

6.2.2 The b-sheet

The b-sheet is the second most common secondary structure in proteins,
consisting of an assembly of b-strands connected by at least three inter-
strand hydrogen bonds. These interstrand hydrogen bonds occur between
the carbonyl and amide NHs of every other residue in the backbone. The
b-strands can be connected in either a parallel or an antiparallel manner,
with different geometries; the parallel orientation is less stable due to
nonplanarity. b-Sheets are composed of b-strands in an extended con-
formation with a slight twist and with interchain hydrogen bonds. The
antiparallel arrangement provides a stronger interstrand stability than
the corresponding parallel. For the parallel arrangement, it is rare to find
fewer than five interacting strands in a motif. b-Sheets can participate in
several different structural motifs, including b-hairpin, Greek key motif,
b-a-b motif and a/b protein folds, such as in a TIM barrel with eight a-
helices and eight parallel b-strands, where the latter form a b-barrel.
a-Helical structures have been pursued in de novo design to a signifi-
cantly larger extent than b-sheet-containing structures. Helix require-
ments are well understood and the hydrogen bonds in helices are
intrachain, and thus the sequences are less likely to form insoluble aggre-
gates, unless they also have a propensity for b-sheet formation. However,
some b-sheet-containing assemblies are described in Section 6.3.5.

6.2.3 Loops, Turns and Templates

In the design of proteins, it is necessary to consider how the secondary
structure elements are connected. In proteins with linear sequences, turns
and loops connect the secondary structural elements, whereas some
artificial proteins have a central scaffold to which the peptide strands
are fixed (template-assembled synthetic proteins, TASPs). Turns and turn
mimetics are briefly introduced in Chapter 3 by Maes and Tourw ´. Thus,
the discussion here will be limited to a few notes. DeGrado and coworkers
have been successful in engineering turns in their de novo -designed
proteins, notably the GPRRG sequence, which also directs antiparallel
dimerization by charge repulsion. Helix nucleators are also described by
Maes and Tourw ´ in Chapter 3.
b-Sheets can be stabilized by incorporation of artificial structures,
especially b-turn mimics (for a review, see [42]). b-Hairpins (in which
antiparallel strands are connected with a reverse turn) can be assembled
with b-turn mimics. Here the reverse turns induce b-sheet structure by