Aromatic rescue of glycine in beta sheets

Glycine is an intrinsically destabilizing residue in beta 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.

Protein variants containing glycine and aromatic residues positioned across beta 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 beta-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.

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