Epitope A encodes significant amino acid changes over time and has also been demonstrated to be an evolving GII.4 blockade epitope using mouse mAbs ( Figure 9A, 9B and [43] ). Epitope A is conformational and is located on the top of the capsid proximal to the HBGA binding pocket. Six variable sites were close to each other in the region of this putative epitope, suggesting that these residues may work in concert to change the local structure of Epitope A. The variable, surface-exposed residues include positions 294, 296-298, 368 and 372. Of note, Epitope A is continuing to evolve in extant strains, whereby the amino acid at position 294 seems to vary extensively in strains from 2008-2010 (amino acid replacements P294A, P294S and P294T have been observed at this position). Epitope B was predicted based upon two variable residues at positions 333 and 382. While these residues are buried in the dimer interface between two chains, the patterns of variation at these sites suggest that they play an important role in the evolution of novel strains, perhaps by evolving replacements that allow the more surface exposed residues in other surface exposed epitopes to dramatically change the physiochemical properties of the amino acid replacements. Residues 340 and 376 make up the variable residues of putative Epitope C. This putative conformation dependent epitope is on the surface and lateral edge of the capsid and is directly proximal to the HBGA binding pocket, suggesting that this epitope may play a role in receptor switching along with Epitope D. Epitope D is comprised Table S2 . doi:10.1371/journal.ppat.1002705.g007 of three variable residues from positions 393-395. In the first reported crystal structure for the GII.4 noroviruses, this region was reported to be a secondary HBGA binding site [16] . However, the location of this epitope on the surface of the capsid, directly proximal to the HBGA binding site, suggests that it likely plays a role in both receptor switching and in escape from herd immunity and perhaps both, simultaneously [13, 21, 40, 43] . Epitope D is close enough to the HBGA binding pocket to contribute to or inhibit carbohydrate binding, and yet variable enough to suggest that it is targeted by the immune response. Putative Epitope E is comprised of variable residues 407, 412 and 413, which are surface exposed regions lateral to the HBGA binding pockets and the other epitopes. These residues vary with every major epidemic strain after 2002, suggesting that it is a hot spot for the emergence of immunologically novel GII.4 strains. Epitope E is a GII.4.2002 blockade antibody epitope [17] . This putative epitope is lateral to the HBGA binding pockets indicating that antibodies are targeting interior regions below the capsid surface, which suggests that other epitopes may be present in the P1 subdomain. A few variable residues do not necessarily identify the boundaries of a putative epitope. Moreover, it is nearly impossible to predict the surface area of a putative epitope by sequence analysis alone. Therefore, we expanded the putative epitopes to include residues within 8 Å of the variable sites from which the epitopes were predicted ( Figure 9B ).