Molecular dynamics approach to probe the antigenicity of PagN – an outer membrane protein of Salmonella Typhi

PagN is a highly immunogenic 27-kDa outer membrane adhesin present in Salmonella Typhi. It plays a major role in the pathogenesis of typhoid fever and has emerged as a strong vaccine candidate. In this report, we predict the three-dimensional structure of PagN and describe the conformational dynamics associated with its four extracellular loops based on two 100-ns molecular dynamics simulations at 300 and 310 K. The formation and deformation of the secondary structures on these loops were also investigated during the simulations which revealed loops L1 and L2 to be highly flexible, whereas the relative flexibility of loops L3 and L4 was minimal. Essential dynamics and principal component analysis deciphered more realistic dynamic behaviours of the loops, particularly at 310 K. Moreover, our epitope predictions suggest that the antigenic peptides for B-cell recognition are located within the loops L1 and L2, while those for T-cell recognition are located within the loops L3 and L4. The binding specificities of the antigenic peptides towards specific human MHC-I and MHC-II HLA alleles closely resembled the stability of the loops L3 and L4 inferred from the simulations. Finally, we identified potential antigenic peptides in the flexible (L1 and L2) as well as stable (L3 and L4) regions of PagN for both B- and T-cell recognitions, which can help in developing effective sub-unit vaccines.