Stereophysicochemical variability plots highlight conserved antigenic areas in Flaviviruses.
BACKGROUND
Flaviviruses, which include Dengue (DV) and West Nile (WN), mutate in response to immune system pressure. Identifying escape mutants, variant progeny that replicate in the presence of neutralizing antibodies, is a common way to identify functionally important residues of viral proteins. However, the mutations typically occur at variable positions on the viral surface that are not essential for viral replication. Methods are needed to determine the true targets of the neutralizing antibodies.


RESULTS
Stereophysicochemical variability plots (SVPs), 3-D images of protein structures colored according to variability, as determined by our PCPMer program, were used to visualize residues conserved in their physical chemical properties (PCPs) near escape mutant positions. The analysis showed 1) that escape mutations in the flavivirus envelope protein are variable residues by our criteria and 2) two escape mutants found at the same position in many flaviviruses sit above clusters of conserved residues from different regions of the linear sequence. Conservation patterns in T-cell epitopes in the NS3- protease suggest a similar mechanism of immune system evasion.


CONCLUSIONS
The SVPs add another dimension to structurally defining the binding sites of neutralizing antibodies. They provide a useful aid for determining antigenically important regions and designing vaccines.
Schein
Catherine H
CH
Sealy Center for Structural Biology, Department of Human Biology, Chemistry and Genetics, University of Texas Medical Branch at Galveston, TX, USA. chschein@utmb.edu
Zhou
Bin
B
Braun
Werner
W
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000956:Antigens, Viral / Q000737:chemistry* / Q000235:genetics; D017124:Conserved Sequence; D005416:Flavivirus / Q000378:metabolism*; D015686:Gene Products, env / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D011487:Protein Conformation; D012984:Software; D015678:Viral Structural Proteins / Q000737:chemistry*
D000956:Antigens, Viral; D015686:Gene Products, env; D015678:Viral Structural Proteins