Aromatic rescue of glycine in β sheets

Abstract

Background: Glycine is an intrinsically destabilizing residue in β sheets. In natural proteins, however, this destabilization can be ‘rescued’ by specific cross-strand pairing with aromatic residues. Here, we present an experimental study of this effect.

Results: Protein variants containing glycine and aromatic residues positioned across β strands in both antiparallel and parallel orientations were studied. The pairing of glycine and phenylalanine across antiparallel strands resulted in a synergistic increase in protein stability. Dramatic differences in stability were observed for the parallel β-sheet mutants, which were dependent upon the type of site occupied by glycine as well as the type of aromatic residue with which it was cross-strand paired.

Conclusions:Experimental results from a series of mutants suggest a thermodynamic benefit for glycine–aromatic pairing across antiparallel β strands, consistent with the prevalence of such pairs in natural proteins. We also demonstrate the specificity of glycine–aromatic interactions across parallel β strands, which defines strand register.