Protein Structure and Evolutionary History Determine Sequence Space   Topology
  Understanding the observed variability in the number of homologs of a gene is a very important, unsolved problem that has broad implications for research into co-evolution of structure and function, gene duplication, pseudogene formation and possibly for emerging diseases. Here we attempt to define and elucidate the reasons behind this observed unevenness in sequence space. We present evidence that sequence variability and functional diversity of a gene or fold family is influenced by certain quantitative characteristics of the protein structure that reflect potential for sequence plasticity i.e. the ability to accept mutation without losing thermodynamic stability. 
Boris Shakhnovich, Eric Deeds, Charles Delisi and Eugene Shakhnovich