Structural Homology of Epitope Binding Mimicry in the Onset of Type 1 Diabetes Mellitus.

Molecular mimicry, where foreign and self-peptides contain similar epitopes, can induce autoimmune responses. Identifying potential molecular mimics and studying their properties is key to understanding the onset of autoimmune diseases such as type 1 diabetes mellitus (T1DM). Previous work identified pairs of infectious epitopes (EINF) and T1DM epitopes (ET1D) that demonstrated sequence homology; however, structural homology was not considered. Correlating sequence homology with structural properties is important for streamlining translational investigation of potential molecular mimics. Therefore, the purpose of this work is to compare sequence homology with structural homology by calculating the structures and electrostatic potentials of 35 pairs of epitopes identified in previous work from our laboratory. For each epitope pair the root mean square deviation (RMSD) was calculated between their predicted structures and their electrostatic potentials were compared. Structures were predicted using the AlphaFold and I-TASSER software programs. We considered a structural match of EINF and ET1D pairs successful if the RMSD was < 1.5 Å. AlphaFold found a 76.5% success rate and I-TASSER, 82.35%. Of the pairs that could not be structurally matched (< 3 residues aligned), AlphaFold found four unique pairs, and I-TASSER found two unique pairs. Therefore, both AlphaFold and I-TASSER agreed on four E INF /E T1D structurally unmatched pairs. Despite structural differences, these four E INF /E T1D pairs show similar electrostatic distributions, indicating that they may still bind to the same protein targets, major histocompatibility complex molecules, for T1DM. These findings suggest that searching for epitope pairs using sequence homology, a much less computationally demanding approach, leads to strong candidates for further study.