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Expanding the fluorescent toolkit with non-canonical amino acids

Award Number: R01GM136996
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: 04/01/2020
PERIOD OF PERFORMANCE END DATE: 03/31/2025

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Expanding the fluorescent toolkit with non-canonical amino acids - PROJECT SUMMARY Fluorescent methods have revolutionized our ability to study biological processes in cellular environments. Despite an ever-expanding fluorescent toolkit, current methods are often limited in their ability to report on dynamic events (e.g. protein-protein interactions, ligand binding, or the flux of metal ions in cells) that underpin a majority of biological processes. The proposed research seeks to address this challenge by combining computational protein design methods with technology allowing the cellular incorporation of fluorescent non-canonical amino acids (fNCAAs) in proteins to generate novel classes of protein-based fluorescent sensors with enhanced properties. Our efforts will focus on developing new protein-based tools in which environmentally sensitive fluorophores— those whose fluorescent properties are modified in response to changes in the surrounding environment—serve as sensors of dynamic cellular processes. The ability to use such dyes to study dynamic processes in cellular environments is often limited by the fact that fluorophores are generally attached to the surfaces of target biomolecules. Alternatively, genetically encoded NCAAs are incorporated directly in the peptide backbone and are therefore uniquely suited to respond to subtle changes within protein scaffolds. This suggests that fNCAAs could serve as a platform for the creation of a novel class of protein-based sensors that dynamically respond to a host of stimuli. However, achievement of this goal would require the ability to identify optimal sites of fNCAA incorporation such that a well-defined change in fluorescence is expected without disrupting natural protein function. We recently structurally characterized proteins containing an fNCAA with a 7-hydroxycoumarin (7-HC) side chain that are responsive to protein-protein and protein-small molecule interactions. These data provide insight into how changes in the environment surrounding the 7-HC fluorophore translate into changes in its spectrum, thereby paving the way for the rational design of fluorescent biosensors of protein-small molecule interactions. To explore this possibility, our recently obtained structural data will serve as inputs to computational protein design methods that will be used to engineer new fluorescent sensors of small molecule metabolites. In a second aim, we will develop highly selective metal ion sensors based on NCAAs containing either 7-HC or 8- hydroxyquinoline (8-HQ) as a side chain. Again, computational protein design methods will be used to sculpt the protein environments surrounding these NCAAs in order to generate new fluorescent proteins that are sensitive to a wide range of biologically relevant metal concentrations and can be selectively produced in cells in a spatiotemporally controlled fashion. Finally, because many existing fNCAAs exhibit fluorescent properties that are not readily amenable to cell-based assays we will expand the toolkit of existing fluorescent NCAAs to include those with enhanced properties that will facilitate the direct study of biological processes in cells.


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 = -$12,048 )
2025	2023	ARIZONA STATE UNIVERSITY	1475 N SCOTTSDALE RD STE 200	SCOTTSDALE	AZ	85257	MARICOPA	USA	Biomedical Research and Research Training	000	4	8/5/2025	NON-COMPETING CONTINUATION	-$12,048
														Subtotal = -$12,048

Issue Date FY: 2023 ( Subtotal = $339,865 )
2023	2023	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Biomedical Research and Research Training	000	4	3/16/2023	NON-COMPETING CONTINUATION	$339,865
														Subtotal = $339,865

Issue Date FY: 2022 ( Subtotal = $340,857 )
2022	2022	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Biomedical Research and Research Training	001	3	6/29/2022	NON-COMPETING CONTINUATION	$34,086
2022	2022	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Biomedical Research and Research Training	000	3	4/1/2022	NON-COMPETING CONTINUATION	$306,771
														Subtotal = $340,857

Issue Date FY: 2021 ( Subtotal = $341,775 )
2021	2021	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Biomedical Research and Research Training	000	2	3/25/2021	NON-COMPETING CONTINUATION	$341,775
														Subtotal = $341,775

Issue Date FY: 2020 ( Subtotal = $342,625 )
2020	2020	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Biomedical Research and Research Training	000	1	3/17/2020	NEW	$342,625
														Subtotal = $342,625

Grand Total All Awards = $1,353,074

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Expanding the fluorescent toolkit with non-canonical amino acids

Award Number: R01GM136996

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: 04/01/2020

PERIOD OF PERFORMANCE END DATE: 03/31/2025

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