# Structural biophysics and molecular design in cellular immunity

> **NIH NIH R35** · UNIVERSITY OF NOTRE DAME · 2024 · $422,550

## Abstract

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 ...

## Key facts

- **NIH application ID:** 10834883
- **Project number:** 5R35GM118166-09
- **Recipient organization:** UNIVERSITY OF NOTRE DAME
- **Principal Investigator:** Brian M Baker
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $422,550
- **Award type:** 5
- **Project period:** 2016-05-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10834883

## Citation

> US National Institutes of Health, RePORTER application 10834883, Structural biophysics and molecular design in cellular immunity (5R35GM118166-09). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10834883. Licensed CC0.

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