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Computer Simulations of Enzymes

Award Number: R01GM061870
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: 07/01/2000
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Computer Simulations of Enzymes - Computer simulations using molecular dynamics (MD) and the combined quantum mechanical/molecular mechanical (QM/MM) approach are capable of describing structures and dynamics of proteins and chemical reactions catalyzed by enzymes. An accurate and computationally efficient energy function is necessary. However, challenges remain: the accuracy of QM method, the compatibility between the electron density of the QM subsystem and classical force fields for the MM subsystem, and the cost of ab initio QM/MM methods capitalizing on the accuracy and reliability of the associated QM approaches. To address these challenges, we have developed a series of ab initio QM/MM approaches on reaction path optimizations and free energy calculations, the QM/MM minimum free-energy path (QM/MM-MFEP) and the QM/MM neural network (QM/MM-NN) methods. This proposal aims to develop further the ab initio QM/MM methodology and its applications to the studies of redox processes in important enzymes, and the construction of ab initio force fields combined with neural network representations. Our long-term goals are to develop and establish accurate first-principles based and density functional theory (DFT) based MD and QM/MM simulation as an equal partner with experiments for the study of enzymes and proteins and to provide insight into chemical and redox processes in biological systems. Our aims are as follows: (1) We aim to make ab initio QM/MM models for much more accurate QM/MM energies, for the QM description and for the electrostatic and vdW interactions between the QM and MM subsystems. (2) We aim to develop a combined computational model to explore the key molecular determinants of the reduction potential variability in metalloproteins. We will provide detailed insight into chemical and redox reaction mechanisms in biological systems, in particular laccases. (3) We aim at the development of accurate force fields of water, and proteins for simulations in biological applications, going beyond the traditional force field forms and limitation in accuracy. The proposed developments will capitalize on the theoretical developments in quantum electronic theory, such as the linear response theory and accurate many-electron approach for non-covalent interactions, and leverage machine-learning methods in data science for biological system simulations. The proposed work will lead to the major advancement of the ab initio QM/MM method and force fields, and insights into the structure-function paradigm for proteins and important redox process and reaction mechanisms in enzymes. In addition, it will also lead to methodology development for design of new drugs and enzyme inhibitors.


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 = $0 )
2026	2022	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Biomedical Research and Research Training	000	20	4/1/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Biomedical Research and Research Training	000	20	8/27/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $359,977 )
2022	2022	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	000	20	9/5/2022	NON-COMPETING CONTINUATION	$359,977
														Subtotal = $359,977

Issue Date FY: 2021 ( Subtotal = $360,392 )
2021	2021	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	000	19	8/16/2021	NON-COMPETING CONTINUATION	$360,392
														Subtotal = $360,392

Issue Date FY: 2020 ( Subtotal = $360,797 )
2020	2020	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	002	18	8/24/2020	NON-COMPETING CONTINUATION	$360,797
2020	2019	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	001	17	5/5/2020	COMPETING CONTINUATION	$0
2020	2017	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	000	16	5/5/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $360,797

Issue Date FY: 2019 ( Subtotal = $341,716 )
2019	2019	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	000	17	8/23/2019	COMPETING CONTINUATION	$341,716
														Subtotal = $341,716

Issue Date FY: 2018 ( Subtotal = $0 )
2018	2017	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	000	16	8/10/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2017 ( Subtotal = $316,026 )
2017	2017	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	000	16	8/24/2017	NON-COMPETING CONTINUATION	$316,026
														Subtotal = $316,026

Issue Date FY: 2016 ( Subtotal = $313,964 )
2016	2016	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	000	15	8/23/2016	NON-COMPETING CONTINUATION	$313,964
														Subtotal = $313,964

Issue Date FY: 2015 ( Subtotal = $311,886 )
2015	2015	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	000	14	9/2/2015	NON-COMPETING CONTINUATION	$311,886
														Subtotal = $311,886

Issue Date FY: 2014 ( Subtotal = $306,927 )
2014	2014	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	002	13	8/28/2014	COMPETING CONTINUATION	$306,927
2014	2012	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	000	12	11/25/2013	NON-COMPETING CONTINUATION	$0
2014	2012	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	001	12	8/26/2014	NON-COMPETING CONTINUATION	$0
														Subtotal = $306,927

Issue Date FY: 2012 ( Subtotal = $304,288 )
2012	2012	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	000	12	12/7/2011	NON-COMPETING CONTINUATION	$273,859
2012	2012	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	001	12	4/17/2012	NON-COMPETING CONTINUATION	$30,429
														Subtotal = $304,288

Issue Date FY: 2011 ( Subtotal = $295,549 )
2011	2011	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	000	11	12/1/2010	NON-COMPETING CONTINUATION	$268,680
2011	2011	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	001	11	6/13/2011	NON-COMPETING CONTINUATION	$26,869
														Subtotal = $295,549

Issue Date FY: 2010 ( Subtotal = $296,327 )
2010	2010	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	001	10	3/5/2010	NON-COMPETING CONTINUATION	$26,939
2010	2010	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	000	10	11/27/2009	NON-COMPETING CONTINUATION	$269,388
														Subtotal = $296,327

Issue Date FY: 2009 ( Subtotal = $299,320 )
2009	2009	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	001	9	11/24/2008	COMPETING CONTINUATION	$299,320
2009	2008	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	000	8	12/2/2008	NON-COMPETING CONTINUATION	$0
														Subtotal = $299,320

Issue Date FY: 2008 ( Subtotal = $231,583 )
2008	2008	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	000	8	12/1/2007	NON-COMPETING CONTINUATION	$231,583
														Subtotal = $231,583

Issue Date FY: 2007 ( Subtotal = $227,078 )
2007	2007	DUKE UNIVERSITY	BOX 104135	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	000	7	11/13/2006	NON-COMPETING CONTINUATION	$227,078
														Subtotal = $227,078

Issue Date FY: 2006 ( Subtotal = $229,642 )
2006	2006	DUKE UNIVERSITY	POST OFFICE BOX 40005	DURHAM	NC	27706	DURHAM	USA	Biomedical Research and Research Training	000	6	11/23/2005	NON-COMPETING CONTINUATION	$229,642
														Subtotal = $229,642

Issue Date FY: 2005 ( Subtotal = $253,440 )
2005	2005	DUKE UNIVERSITY	POST OFFICE BOX 40005	DURHAM	NC	27706	DURHAM	USA	Biomedical Research and Research Training	000	5	11/26/2004	COMPETING CONTINUATION	$253,440
														Subtotal = $253,440

Issue Date FY: 2003 ( Subtotal = $143,733 )
2003	2003	DUKE UNIVERSITY	POST OFFICE BOX 40005	DURHAM	NC	27706	DURHAM	USA	Cell Biology and Biophysics Research	000	4	6/9/2003	NON-COMPETING CONTINUATION	$143,733
														Subtotal = $143,733

Issue Date FY: 2002 ( Subtotal = $167,067 )
2002	2002	DUKE UNIVERSITY	POST OFFICE BOX 40005	DURHAM	NC	27706	DURHAM	USA	Cell Biology and Biophysics Research	000	3	6/24/2002	NON-COMPETING CONTINUATION	$167,067
														Subtotal = $167,067

Grand Total All Awards = $5,453,845

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Computer Simulations of Enzymes

Award Number: R01GM061870

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: 07/01/2000

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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