QUANTIFICATION OF TERTIARY STRUCTURAL CONSERVATION DESPITE PRIMARY SEQUENCE DRIFT IN THE GLOBIN FOLD

The globin family of protein structures was the first for which it was recognized that tertiary structure can be highly conserved even when primary sequences have diverged to a virtually undetectable level of s imilarity. This principle of structural inertia in molecular evolution is now evident for many other protein families. We have performed a s ystematic comparison of the sequences and structures of 6 representati ve hemoglobin subunits as diverse in origin as plants, clams, and huma ns. Our analysis is based on a 97-residue helical core in common to al l 6 structures. Amino acid sequence identities range from 12.4% to 42. 3% in pairwise comparisons, and, despite these variations, the maximal RMS deviation in alpha-carbon positions is 3.02 Angstrom. Overall, se quence similarity and structural deviation are significantly anticorre lated, with a correlation coefficient of -0.71, but for a set of struc tures having under 20% pairwise identity, this anticorrelation falls t o -0.38, which emphasizes the weak connection between a specific seque nce and the tertiary fold. There is substantial variability in structu re outside the helical core, and functional characteristics of these g lobins also differ appreciably. Nevertheless, despite variations in de tail that the sequence dissimilarities and functional differences impl y, the core structures of these globins remain remarkably preserved.