Aromatic rescue of glycine in beta sheets

Background: Glycine is an intrinsically destabilizing residue in beta sheet s. In natural proteins, however, this destabilization can be 'rescued' by s pecific cross-strand pairing with aromatic residues. Here, we present an ex perimental study of this effect. Results: Protein variants containing glycine and aromatic residues position ed across beta strands in both antiparallel and parallel orientations were studied. The pairing of glycine and phenylalanine across antiparallel stran ds resulted in a synergistic increase in protein stability. Dramatic differ ences 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 ty pe of aromatic residue with which it was cross-strand paired. Conclusions: Experimental results from a series of mutants suggest a thermo dynamic benefit for glycine-aromatic pairing across antiparallel beta stran ds, consistent with the prevalence of such pairs in natural proteins. We al so demonstrate the specificity of glycine-aromatic interactions across para llel beta strands, which defines strand register.