Modeling of receptor mimics that inhibit superantigen pathogenesis

Abstract

Staphylococcal enterotoxins SEB and SEC3 and toxic shock syndrome toxin TSST-1 act as superantigens by overstimulating the human immune system and thereby compromise host defense. The mechanism of pathogenesis is explained on the basis of superantigen binding to the MHC class II receptor on the antigen presenting cell and to the T cell receptor (TcR) on the T cell. SEB, SEC3 and TSST-1 bind as intact proteins and make contacts with the alpha1 subdomain (DRalpha) of MHC class II and Vbeta subdomain of TcR. SEB, SEC3 and TSST-1 show specificities for different TcRVbeta isoforms. We have designed three different chimeras linking the same DRalpha with different TcRVbeta isoforms to specifically target SEB, SEC3 and TSST-1 and inhibit their pathogenesis. Here, we show by molecular modeling that the DRalpha, TcRVbeta and linker of a given chimera interact with the target superantigen in a type-specific manner. An initial model of the complex is constructed on the basis of observed inter-molecular contacts between DRalpha/TcRVbeta and the superantigens. A constant temperature (300 K) 200 ps molecular dynamics is performed to sample different conformations of a chimera-superantigen complex by utilizing the flexibility of the (GSTAPPA)(2) linker while maintaining the native folds of superantigen, DRalpha and TcRVbeta and the observed intermolecular contacts. After equilibration, 100 molecular dynamic snapshots are minimized and analyzed. This provides descriptions of various pairwise interactions at the contact interface in the complex and important clues on single site mutations on the chimera that may enhance the stability of a given superantigen-chimera complex.