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Modeling Transition Metal Ion Binding to Proteins

Award Number: R01GM130641
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: 09/01/2019
PERIOD OF PERFORMANCE END DATE: 07/31/2028

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Modeling Transition Metal Ion Binding to Proteins - Project Summary/Abstract Transition metal (TM) ions play myriad roles in biology and are present in >30% of structures in the PDB yet the accurate computational modeling of these ions is less evolved than for the “organic” framework of proteins. Hence, the simulation of metalloprotein structure, function and dynamics lags behind related studies on proteins that do not contain TM ions. To address this issue multiple groups have built models validated using varying criteria making it difficult to focus on best practices. Because of this gap in the modeling of TM ions important biological problems associated with TM ion homeostasis, metal center assembly, TM/drug interactions, dynamics of ligand association and product dissociation in metalloenzymes, attacking pathogens using nutritional immunity via TM sequestration near infection sites, role of Fe(II)/Fe(III) in ferroptosis etc. remain a significant challenge to computationally address. Through the systematic development of robust computational models of TMs, hypotheses can be formed to address problems focused on TM ion biology at a level currently available for systems lacking TM ions. We propose that we can fundamentally advance the study of transition metal (TM) containing biological systems by developing a freely available centralized software “hub” containing multiple validated classical force field models for TM ions that will facilitate the routine and accurate modeling of the structure and thermodynamics of TMs bound to proteins and in aqueous solution. Our long-term goal is to advance TM modeling approaches, place them into the widely used AMBER simulation package and then validate and disseminate the various methodologies to address problems involving metalloproteins by both the experimental and computational communities. Moreover, in this proposal we hypothesize that our models will enhance our ability to design metal binding sites and provide molecular-level insights into TM ion transport. The fundamental biophysical and biochemical questions we are addressing are what controls the structure, function and dynamics of TM ion complexation and TM ion transport in proteins. Building on our success with developing class-leading bonded metal ion force fields we will create next generation models that can be exploited in understanding the structural and functional role of TMs in biology.


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 = $329,648 )
2025	2025	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Biomedical Research and Research Training	002	6	7/29/2025	NON-COMPETING CONTINUATION	$329,648
2025	2024	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Biomedical Research and Research Training	001	5	3/24/2025	COMPETING CONTINUATION	$138
2025	2022	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	000	4	3/24/2025	NON-COMPETING CONTINUATION	-$138
														Subtotal = $329,648

Issue Date FY: 2024 ( Subtotal = $344,898 )
2024	2024	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Biomedical Research and Research Training	001	5	8/16/2024	COMPETING CONTINUATION	$344,898
2024	2022	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	000	4	2/2/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $344,898

Issue Date FY: 2022 ( Subtotal = $320,515 )
2022	2022	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	000	4	6/22/2022	NON-COMPETING CONTINUATION	$320,515
														Subtotal = $320,515

Issue Date FY: 2021 ( Subtotal = $529,758 )
2021	2021	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	001	3	7/16/2021	SUPPLEMENT FOR EXPANSION	$209,881
2021	2021	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	000	3	6/7/2021	NON-COMPETING CONTINUATION	$319,877
														Subtotal = $529,758

Issue Date FY: 2020 ( Subtotal = $319,909 )
2020	2020	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	000	2	6/30/2020	NON-COMPETING CONTINUATION	$319,909
														Subtotal = $319,909

Issue Date FY: 2019 ( Subtotal = $319,659 )
2019	2019	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Biomedical Research and Research Training	000	1	8/27/2019	NEW	$319,659
														Subtotal = $319,659

Grand Total All Awards = $2,164,387

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Modeling Transition Metal Ion Binding to Proteins

Award Number: R01GM130641

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: 09/01/2019

PERIOD OF PERFORMANCE END DATE: 07/31/2028

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