Structural biophysics and molecular design in cellular immunity

点击翻译按钮获取中文摘要

Abstract Our NIGMS-funded research emphasizes the interface between structural biology, molecular biophysics, and immunology. Broadly speaking, we aim to connect the fundamental physical principles that govern protein behavior with function in the immune system, relying on a wide variety of approaches in biophysics, structural biology, computational biochemistry, and molecular immunology. In addition to providing mechanistic insight into immunology, our work in this interface has been instructional for addressing basic rules of biomolecular recognition and other protein behavior, as well as in the modeling and design of complex systems. In this renewal, we propose to continue this interdisciplinary focus. Our studies emphasize T cell receptors (TCRs) and their ligands, short peptides bound and “presented” by major histocompatibility complex proteins (peptide/MHC complexes). TCR recognition of peptide/MHC complexes is the cornerstone of cellular immunity, as it defines specificity and initiates the signaling that leads to T cell immune responses. Owing to the high diversity in both receptor and ligand, as well as the myriad of processes in which these molecules participate, the TCRs- peptide/MHC interaction is recognized as one of the most complex in biology. Deconstructing how specificity emerges in the face of this extraordinary complexity, learning how to predict and manipulate TCR recognition properties, and understanding the biophysics of T cell signaling processes remains at the core of our studies. We are motivated not only by the desire to gain further mechanistic insight, but also by the growth of new therapeutic approaches such as gene-engineered T cells and peptide-based vaccines. While there have been immunotherapy successes, there have also been significant complications and confounding outcomes. It is widely understood that an improved understanding of the fundamentals of immune recognition is needed for such therapies to reach their potential. Our goals for the next five years include improving our understanding of the mechanisms of TCR cross-reactivity and specificity, with an eventual goal of using structural information and modeling to identify cross-reactive ligands. Advances here will require concomitant improvements in our ability to model and score suboptimal (or as we call them, “sloppy”) protein-protein interfaces, which is a major part of our focus. We also plan to assess the mechanism of enigmatic “catch bonds” in TCR-peptide/MHC interfaces through the lens of physical chemistry, a view which has been largely absent from the discussion of catch bonds in immunology. We also aim to bring elements of physical chemistry and structural biology into predictions of immunogenicity, tackling this by considering the biophysics of protein-protein molecular recognition. Lastly, we aim to continue our work on dynamic allostery, studying how protein dynamics contribute to immune recognition and the still poorly-understood mechanism of T cell triggering. Our work remains highly collaborative and interdisciplinary, allowing it to impact multiple fields in molecular and cellular immunology and protein biophysics.