Biophysical Characterization of Novel Protein Dynamics in the Adaptive Immune System

Biophysics is the study of the form and function of life’s machines. It combines the fields of biology, biochemistry, physics, and mathematics to study microscopic phenomena. The components of the immune system that confer a response are full of complexity. However, this complexity is simplified if we recognize that their processes evolved harmonically. By learning the fundamental biophysics of aspects of the adaptive immune system, we can establish the basis for the complexities of the immune response. We study these fundamentals through a cornerstone of adaptive immunity: the protein-protein interaction between the specialized receptors of T cells of the immune system and the complex of a peptide presented by a major histocompatibility complex (MHC) protein. T cell receptors (TCRs) bind the composite interface of peptide/MHC (pMHC) proteins as a necessary first step to the T cell immune response. Many studies of TCR-pMHC interactions have provided considerable insight into the determinants of TCR recognition, including TCR preferences for peptides and the ‘rules’ of TCR binding and subsequent immune responses. These central ideas have been integrated into various approaches to predict TCR specificity and peptide immunogenicity. However, there exist many exceptions to these rules, such as peptide conformational adaptability and alternative TCR engagement. Here, we use a combination of experimental and computational biophysics techniques to determine the mechanism and minimal determinants of a peptide conformational change and the superantigenic capabilities of the SARS-CoV-2 spike protein. As new and further advanced techniques in biophysical analysis arise, especially with the introduction of artificial intelligence in computational methodology, it is imperative that we approach these studies with insight and a realistic understanding of the scope of our research. If we can define the biophysics and inherent dynamics of the proteins that induce an immunological response, we can predict and control the functions of these molecules, with broad implications for immunotherapy and the field of immunology.