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Understanding Essential Protein Dynamics through the Anharmonic Properties of Thermally Excited Vibrations

Award Number: R01GM148622
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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The selectivity of orthosteric drugs is often limited by the structural similarity of their binding sites in homologous proteins, while allosteric binding sites are far less conserved. This allows allosteric drugs to bind a target protein with higher selectivity, which reduces the potential for side-effects and lowers drug toxicity. However, allosteric drug discoveries have been limited to serendipitous observations because rational allosteric drug design strategies face several inherent challenges. These challenges are directly related to current limits in the predictability of protein conformational fluctuations and collective dynamics that are central to the mechanisms of allosteric drugs. The objective of this project is the development of computational methods to facilitate the rational design of allosteric drugs via predictions of protein conformational fluctuations and collective dynamics from all-atom simulations. In principle, all-atom molecular dynamics simulations can directly explore protein conformational dynamics but require sampling on timescales of milliseconds to seconds for systems of pharmacological interest. Even with state-of-the-art enhanced sampling techniques, the associated computational costs and hardware requirements (special purpose computers, national supercomputers, large distributed computing networks) limit such applications to a small number of systems. This project aims to make the computational discovery of allosteric mechanisms in proteins more efficient and achievable with computer hardware available in most research laboratories and universities. To this end, the methods developed for this project maximize the information on inherent protein dynamics that can be extracted from molecular dynamics simulations. These methods will initially be applied to identify allosteric mechanisms in matrix metallo-proteinases (MMPs), which represent a family of structurally homologous proteins involved in the degradation of the extracellular matrix. Several members of the MMP family have been identified as drug targets in the context of chronic inflammatory disease and cancer metastasis. MMPs feature a highly conserved catalytic center, which results in a low selectivity of orthosteric small molecule inhibitors for individual MMPs and limits their therapeutic use. This project aims to identify allosteric mechanisms in MMPs that enable the targeted development of highly selective allosteric MMP inhibitors as potential drug candidates. The methods developed for this project are general and not specific to MMPs. They will thus be applicable for the identification of allosteric mechanisms in other drug target proteins and will be made available as open- source software.


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: 2024 ( Subtotal = $223,270 )
2024	2024	ARIZONA STATE UNIVERSITY	660 S MILL AVENUE STE 204	TEMPE	AZ	85281	MARICOPA	USA	Biomedical Research and Research Training	002	2	6/18/2024	NON-COMPETING CONTINUATION	$22,327
2024	2024	ARIZONA STATE UNIVERSITY	660 S MILL AVENUE STE 204	TEMPE	AZ	85281	MARICOPA	USA	Biomedical Research and Research Training	001	2	2/21/2024	NON-COMPETING CONTINUATION	$200,943
2024	2023	ARIZONA STATE UNIVERSITY	660 S MILL AVENUE STE 204	TEMPE	AZ	85281	MARICOPA	USA	Biomedical Research and Research Training	000	1	11/30/2023	NEW	$0
														Subtotal = $223,270

Issue Date FY: 2023 ( Subtotal = $224,175 )
2023	2023	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Biomedical Research and Research Training	000	1	2/9/2023	NEW	$224,175
														Subtotal = $224,175

Grand Total All Awards = $447,445

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Understanding Essential Protein Dynamics through the Anharmonic Properties of Thermally Excited Vibrations

Award Number: R01GM148622

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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