Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Macromolecular Conformational Heterogeneity

Award Number: R35GM131710
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: 05/01/2019
PERIOD OF PERFORMANCE END DATE: 04/30/2029

Group Awards By:

View Award Description

Macromolecular Conformational Heterogeneity - Project Summary Biological macromolecules exhibit an amazing degree of conformational heterogeneity as required for their various functions. This heterogeneity is inherent in almost all biological macromolecules and is influenced by interactions with ions, solutes, and other macromolecules. An understanding of the conformational properties of macromolecules and their structure-function relationships is essential to facilitate drug discovery. To this end, our laboratory has focused on a comprehensive research program that includes optimizing and extending empirical atomic force fields for biological and drug-like molecules, developing novel conformational and solute sampling methods and applying those tools in collaborative studies on systems of biological and therapeutic relevance. Biological systems to be studied include the role of Mg2+ ions in RNA folding and on conformational ensembles of RNA, glycan conformational properties and the role of glycoproteins in immune response involving antibodies (Ab) and Fcγ receptors such as FcγRIIIa and FcεRIγ. Interactions between Ab Fc and FcγRIIIa and interactions between Fcγ receptors will be investigated to reveal their contribution towards intracellular phosphorylation and downstream signaling. Methods developments will further optimize and extend the additive (nonpolarizable) CHARMM36 and polarizable classical Drude oscillator force fields (FF). Work on the additive FF will involve the explicit optimization of the off-diagonal Lennard-Jones (LJ) terms to overcome limitations in the use of combining rules. Drude FF work will involve extending the coverage of chemical space including non-standard amino acids, nucleic acids, and carbohydrates, as well as drug-like molecules in the context of the Drude General Force Field (DGenFF). In addition, advances in the accuracy of the Drude FF will include improved treatment of off-diagonal LJ and non-bonded Thole shielding interactions, improved treatment of ions in biological systems, and additional optimization of the protein and nucleic acid parameters of the FF targeting the equilibrium between folded and unfolded states of peptides and short oligonucleotides. This optimization will use enhanced sampling to facilitate generation of conformational ensembles required to apply parameter reweighting approaches. Improved conformational sampling of macromolecules will be achieved using generative deep neural nets (DNN) for the identification of reaction coordinates in conjunction with metadynamics as well as non-equilibrium simulation methods targeting specific degrees of freedom with emphasis on oligonucleotides and polysaccharides. Our solute sampling approach based on the oscillating chemical potential μex Grand-Canonical Monte Carlo/Molecular Dynamics method will be extended to large systems (> 1 million atoms) through efficient use of GPUs, improved treatment of long-range interactions, and the use of the polarizable Drude FF. These developments will be implemented in the site-identification of ligand competitive saturation (SILCS) method to estimate pH dependence of ligand binding, the role of water in drug binding, and ligand koff rates.


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 = $746,909 )
2026	2026	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	8	4/29/2026	NON-COMPETING CONTINUATION	$746,909
														Subtotal = $746,909

Issue Date FY: 2025 ( Subtotal = $746,909 )
2025	2025	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Biomedical Research and Research Training	002	7	5/22/2025	NON-COMPETING CONTINUATION	$746,909
2025	2024	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	6	11/4/2024	COMPETING CONTINUATION	$0
2025	2023	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Biomedical Research and Research Training	001	5	2/19/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $746,909

Issue Date FY: 2024 ( Subtotal = $746,909 )
2024	2024	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	6	4/3/2024	COMPETING CONTINUATION	$746,909
														Subtotal = $746,909

Issue Date FY: 2023 ( Subtotal = $722,975 )
2023	2023	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	5	4/4/2023	NON-COMPETING CONTINUATION	$722,975
														Subtotal = $722,975

Issue Date FY: 2022 ( Subtotal = $932,975 )
2022	2022	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Biomedical Research and Research Training	001	4	6/27/2022	NON-COMPETING CONTINUATION	$72,298
2022	2022	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	4	3/24/2022	NON-COMPETING CONTINUATION	$650,677
2022	2022	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Biomedical Research and Research Training	002	4	8/23/2022	SUPPLEMENT FOR EXPANSION	$210,000
														Subtotal = $932,975

Issue Date FY: 2021 ( Subtotal = $722,975 )
2021	2021	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	3	4/16/2021	NON-COMPETING CONTINUATION	$722,975
														Subtotal = $722,975

Issue Date FY: 2020 ( Subtotal = $722,975 )
2020	2020	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	2	4/17/2020	NON-COMPETING CONTINUATION	$722,975
														Subtotal = $722,975

Issue Date FY: 2019 ( Subtotal = $761,483 )
2019	2019	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Biomedical Research and Research Training	001	1	9/25/2019	SUPPLEMENT FOR EXPANSION	$105,288
2019	2019	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	1	4/23/2019	NEW	$656,195
														Subtotal = $761,483

Grand Total All Awards = $6,104,110

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Macromolecular Conformational Heterogeneity

Award Number: R35GM131710

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: 05/01/2019

PERIOD OF PERFORMANCE END DATE: 04/30/2029

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer