The response of protein structures to amino-acid sequence changes

Abstract

The general response of protein structures to mutations, insertions and deletions is conformational change. Comparisons of related proteins show that a large part of the polypeptide chain retains its basic folding pattern. This ‘core’ of the structures comprises major elements of secondary structure and residues flanking them, including active-site peptides. The core may amount to as little as 40% of the structure for distantly related proteins, but is 90 % or more for proteins with amino-acid sequence homologies of 50 % or more. There is a direct relation between the root mean square deviation of the main-chain atoms of the core residues of a pair of proteins and the overall amino-acid sequence homology. The deviation primarily reflects the shifts and rotations of packed secondary structures with respect to one another. For distantly related proteins, shifts of 3-5 Å (1 Å = 10 ^-1 nm = 10 ^-10 m) are typical and shifts of up to 7 Å have been observed. For proteins with sequence homologies of 50% or more the shifts are much smaller, lying in the range 0.3- 1.5 Å. Such closely related proteins are also characterized by a conservation of over 85% of the conformational angles of the backbone and of the side chains of unmutated residues. These observations suggest that successful model building of an unknown protein structure depends on knowing the structure of a reasonably close relative. As an application of these results we propose a model for the V _L and V _H domains of the antilysozyme antibody D1.3, the crystal structure determination of which is in progress.