Structural Constraints on Residue Substitution

Abstract

Protein sequences are clearly grouped into families related by evolution. Divergence of protein sequences proceeds by random mutation at the gene level and natural selection at the level of protein structure and function. It is well established that the protein folding “code” is highly degenerate, in that many different sequences (for example, less than 20% identical) can adopt the same general fold. However, on analysis of homologous sequences it is found that most families have distinct, conserved, “sequence fingerprints” that define their tertiary fold. Much recent work has attempted to identify these “determinants” of a fold, either by analysis of sets of aligned sequences or three-dimensional structures, or through mutagenesis experiments. These sources of information are highly complementary, and can be used together to model and predict the effects of local mutations, or to predict the fold of a protein of unknown structure. This chapter attempts to highlight some of the important features of protein structure, as identified by analysis of naturally observed substitutions in families of related proteins.