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Elucidating the dynamical and structural molecular factors at the origin of non-enzymatic protein-protein and protein-DNA cross-links

Award Number: R35GM150409
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: 08/01/2023
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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Elucidating the dynamical and structural molecular factors at the origin of non-enzymatic protein-protein and protein-DNA cross-links - Project Summary Non-enzymatic protein-protein and protein-DNA cross-links are deleterious post-translational modifications that have been associated with many severe pathologies, including cancer metasta- sis, retinopathy, chronic renal failure, skin and bone disorders, aging, diabetes, Alzheimer’s, Par- kinson’s and cardiovascular diseases. However, the development of therapeutic strategies is hin- dered by our poor understanding of their formation. We propose to address this gap in knowledge using computational methods based on intrinsic electric field calculations. Our goal is to identify the structural and dynamical molecular factors at the origin of the formation of non-enzymatic protein-protein and protein-DNA cross-links. We focus our study on sugar-mediated cross-links, initiated by glycation reactions, as it has been shown to occur in a broad range of systems. We hypothesize that partial depletion of the protein (or DNA) hydration layer exposes side chains (or nucleobases) to surrounding carbohydrates. This facilitates glycation reactions whereby reducing sugars (glucose) react with the free amine groups. Glycated proteins and DNA then have enhanced ability to form adducts, altering their biofunction. Our proposed research seeks to provide a molecular interpretation of sugar-mediated cross-link formation and can be divided into three thrusts ; each of which with the potential to expand into a standalone research direction. First, we propose to characterize the density of the hydration layer of healthy and pathological proteins and DNA strands known to aggregate (collagen, elastin and α-synuclein) at the quan- tum level. Our preliminary data on mineralized collagen systems show that water adsorption is controlled by the nature of the environment rather than the nature of the adsorption site, consistent with experimental observations. This suggests that the density functional theory protocol we de- veloped for this study is suitable for the characterization of macromolecule-water interactions. Second, we propose to model carbohydrate reactivity in dehydrated and hydrated biomole- cules, as a proxy for non-enzymatic glycation reactions. The novelty of our approach is to intro- duce accurate reactivity information in classical molecular dynamics simulations using intrinsic electric fields as a metric for bond formation. Our preliminary data verify the feasibility of such study and include the development of an open-source code that allows this type of calculations. Finally, we propose to integrate our atomistic data into a microscopic kinetic model of protein- protein and protein-DNA cross-linking processes. With this model, we aim to predict the critical density, location, cooperativity and strength of cross-links that are associated with known patho- logies, paving the way towards the identification of therapeutic points of intervention.


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: 2026 ( Subtotal = $385,103 )
2026	2026	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Biomedical Research and Research Training	000	4	7/1/2026	NON-COMPETING CONTINUATION	$385,103
														Subtotal = $385,103

Issue Date FY: 2025 ( Subtotal = $380,717 )
2025	2025	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Biomedical Research and Research Training	000	3	6/30/2025	NON-COMPETING CONTINUATION	$380,717
														Subtotal = $380,717

Issue Date FY: 2024 ( Subtotal = $381,278 )
2024	2024	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Biomedical Research and Research Training	000	2	6/26/2024	NON-COMPETING CONTINUATION	$381,278
														Subtotal = $381,278

Issue Date FY: 2023 ( Subtotal = $381,824 )
2023	2023	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Biomedical Research and Research Training	000	1	7/26/2023	NEW	$381,824
														Subtotal = $381,824

Grand Total All Awards = $1,528,922

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Elucidating the dynamical and structural molecular factors at the origin of non-enzymatic protein-protein and protein-DNA cross-links

Award Number: R35GM150409

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: 08/01/2023

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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