A Miniature Protein Stabilized by a Cation−π Interaction Network

The
design of folded miniature proteins is predicated on establishing
noncovalent interactions that direct the self-assembly of discrete
thermostable tertiary structures. In this work, we describe how a
network of cation−π interactions present in proteins
containing “WSXWS motifs” can be emulated to stabilize
the core of a miniature protein. This 19-residue protein sequence
recapitulates a set of interdigitated arginine and tryptophan residues
that stabilize a distinctive β-strand:loop:PPII-helix topology.
Validation of the compact fold determined by NMR was carried out by
mutagenesis of the cation−π network and by comparison
to the corresponding disulfide-bridged structure. These results support
the involvement of a coordinated set of cation−π interactions
that stabilize the tertiary structure.