Thursday, June 19, 2025 6/19/2025

Structural biophysics and molecular design in cellular immunity

Award Number: R35GM118166
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2016
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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Structural biophysics and molecular design in cellular immunity - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $422,550 )
2025	2025	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Biomedical Research and Research Training	001	10	4/21/2025	NON-COMPETING CONTINUATION	$422,550
2025	2024	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Biomedical Research and Research Training	000	9	11/6/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $422,550

Issue Date FY: 2024 ( Subtotal = $422,550 )
2024	2024	UNIVERSITY OF NOTRE DAME DU LAC	836 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Biomedical Research and Research Training	000	9	5/22/2024	NON-COMPETING CONTINUATION	$422,550
														Subtotal = $422,550

Issue Date FY: 2023 ( Subtotal = $652,965 )
2023	2023	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Biomedical Research and Research Training	001	8	5/23/2023	SUPPLEMENT FOR EXPANSION	$230,415
2023	2023	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Biomedical Research and Research Training	000	8	5/1/2023	NON-COMPETING CONTINUATION	$422,550
														Subtotal = $652,965

Issue Date FY: 2022 ( Subtotal = $422,550 )
2022	2022	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Biomedical Research and Research Training	001	7	6/27/2022	NON-COMPETING CONTINUATION	$42,255
2022	2022	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Biomedical Research and Research Training	000	7	4/15/2022	NON-COMPETING CONTINUATION	$380,295
														Subtotal = $422,550

Issue Date FY: 2021 ( Subtotal = $422,550 )
2021	2021	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Biomedical Research and Research Training	000	6	4/12/2021	COMPETING CONTINUATION	$422,550
2021	2020	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Biomedical Research and Research Training	001	5	9/4/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $422,550

Issue Date FY: 2020 ( Subtotal = $606,137 )
2020	2020	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Biomedical Research and Research Training	000	5	4/6/2020	NON-COMPETING CONTINUATION	$394,284
2020	2020	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Biomedical Research and Research Training	001	5	6/1/2020	SUPPLEMENT FOR EXPANSION	$211,853
														Subtotal = $606,137

Issue Date FY: 2019 ( Subtotal = $394,284 )
2019	2019	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Biomedical Research and Research Training	000	4	4/4/2019	NON-COMPETING CONTINUATION	$394,284
														Subtotal = $394,284

Issue Date FY: 2018 ( Subtotal = $394,284 )
2018	2018	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Biomedical Research and Research Training	000	3	4/25/2018	NON-COMPETING CONTINUATION	$394,284
														Subtotal = $394,284

Issue Date FY: 2017 ( Subtotal = $394,284 )
2017	2017	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Biomedical Research and Research Training	001	2	6/15/2017	NON-COMPETING CONTINUATION	$39,429
2017	2017	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Biomedical Research and Research Training	000	2	4/17/2017	NON-COMPETING CONTINUATION	$354,855
														Subtotal = $394,284

Issue Date FY: 2016 ( Subtotal = $246,133 )
2016	2016	UNIVERSITY OF NOTRE DAME	801 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Biomedical Research and Research Training	001	1	8/19/2016	SUPPLEMENT FOR EXPANSION	$76,931
2016	2016	UNIVERSITY OF NOTRE DAME	801 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Biomedical Research and Research Training	000	1	4/21/2016	NEW	$169,202
														Subtotal = $246,133

Grand Total All Awards = $4,378,287

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Structural biophysics and molecular design in cellular immunity

Award Number: R35GM118166

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/01/2016

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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