A rapid method for exploring the protein structure universe

We have developed an automatic protein fingerprinting method for the evalua tion of protein structural similarities based on secondary structure elemen t compositions, spatial arrangements, lengths, and topologies, This method can rapidly identify proteins sharing structural homologies as we demonstra te with five test cases: the globins, the mammalian trypsinlike serine prot eases, the immunoglobulins, the cupredoxins, and the actinlike ATPase domai n-containing proteins. Principal components analysis of the similarity dist ance matrix calculated from an all-by-all comparison of 1,031 unique chains in the Protein Data Bank has produced a distribution of structures within a high-dimensional structural space. Fifty percent of the variance observed for this distribution is bounded by six axes, two of which encode structur al variability within two large families, the immunoglobulins and the tryps inlike serine proteases, Many aspects of the spatial distribution remain st able upon reduction of the database to 140 proteins with minimal family ove rlap. The axes correlated with specific structural families are no longer o bserved. A clear hierarchy of organization is seen in the arrangement of pr otein structures in the universe. At the highest level, protein structures populate regions corresponding to the all-alpha, all-beta, and alpha/beta s uperfamilies, Large protein families are arranged along family-specific axe s, forming local densely populated regions within the space. The lowest lev el of organization is intrafamilial; homologous structures are ordered by v ariations in peripheral secondary structure elements or by conformational s hifts in the tertiary structure. Proteins 1999; 34:317-332, (C) 1999Wiley-L iss, Inc.