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Humoral immune responses against the malaria parasite are an important component of a protective immune response. Antibodies are often directed towards conformational epitopes, and the native structure of the antigenic region is usually critical for antibody recognition. We examined the structural features of various Plasmodium antigens that may impact on epitope location, by performing a comprehensive analysis of known and modelled structures from P. falciparum. Examining the location of known polymorphisms over all available structures, we observed a strong propensity for polymorphic residues to be exposed on the surface and to occur in particular secondary structure segments such as hydrogen-bonded turns. We also utilised established prediction algorithms for B-cell epitopes and MHC class II binding peptides, examining predicted epitopes in relation to known polymorphic sites within structured regions. Finally, we used the available structures to examine polymorphic hotspots and Tajima’s D values using a spatial averaging approach. We identified a region of PfAMA1 involving both domains II and III under a high degree of balancing selection relative to the rest of the protein. In summary, we developed general methods for examining how sequence-based features relate to one another in three-dimensional space and applied these methods to key P. falciparum antigens.
Funding was provided by the National Health and Medical Research Council (NHMRC) of Australia including Fellowships to JSR (APP1037722) and JGB (APP1077636), Project (APP1125788) and Program (APP1092789) grants. Support was provided through Monash University (Australian Postgraduate Award to AJG) and the University of Melbourne (Melbourne International Fee Remission Scholarship and Melbourne International Research Scholarship to VI). Te Burnet Institute is supported by the NHMRC Independent Research Institutes Infrastructure Support Scheme, and a Victoria State Government Operational Infrastructure Support grant. Funding was also provided by National Institutes of Health grants P41 GM109824 and R01 GM083960.