Spatial, sequence-order-independent structural comparison of a/ß proteins: Evolutionaiy implications

We present a unique sequence-order independent approach which allows examination of three dimensional structures, searching for spatially similar substructural motifs. If the amino acids composing the motifs are contiguous in the primary chain, that is, they follow each other in the sequence, a common ancestor and a divergent evolutionary process may be implied. On the other hand, if the three-dimensional substructural motif consists of amino acids whose positions in the sequences vary between the different proteins, a convergent evolution might have taken place. Starting from different, ancient sequences, mutations may have occurred that brought about formation and conservation of a truly structural motif. Such a motif might be particularly suitable for fulfilling a specific function. Clearly, in order to be able to carry out such a task one needs a technique which allows comparisons of protein structures absolutely independent of their amino acid sequence-order. Our novel, efficient, computer vision based technique treats atoms (residues) as unconnected points in space, using strictly the atomic (either all atoms or only the Ca atoms) coordinates. The order of the residues is completely disregarded. Detection, cataloging and analysis of “real” three-dimensional, sequence-order independent motifs in the crystallographic database is expected to be an invaluable tool for protein folding. Here we demonstrate the power of the technique by applying it to a/(S proteins. Our studies indicate that for some of the proteins, the “classical” structural alignments (conserving the amino acid order) are the optimal ones. Nevertheless, for others, truly spatial (out of sequential-order) amino acid equivalencing results in a better geometrical match.