The prediction of five putative epitopes allowed us to gain several important insights into GII.4 norovirus evolution: 1) Discrete sites of variation occur on the GII.4 norovirus capsid, either directly on the surface or lateral to the HBGA binding sites; 2) Secondary variable sites are within 8 Å of the primary variable sites, and these secondary sites could also contribute to epitope remodeling; 3) Many of the putative expanded epitopes overlap, suggesting that two or more highly variable epitopes may work in concert to escape from an antibody response; 4) Putative epitopes that are buried may exert an effect on the structure by altering the interior fold space, allowing unconventional replacements to be tolerated; 5) An underlying amino acid network likely preserves the functional core of the capsid proteins by regulating the variable residues above them; and 6) Escape and HBGA binding may be intimately linked via the underlying regulatory network of amino acids that preserve the functional integrity of the capsid core.