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Combining Molecular Simulations and Biophysical Methods to Characterize Conformational Dynamics of the HIV-1 Envelope Glycoprotein

Award Number: R01AI178833
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/10/2023
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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Combining Molecular Simulations and Biophysical Methods to Characterize Conformational Dynamics of the HIV-1 Envelope Glycoprotein - PROJECT SUMMARY The HIV-1 envelope glycoprotein spike (Env) mediates viral entry into target cells. Because Env is the only viral protein on the virion surface, it is central to the development of potential vaccines and small-molecule entry inhibitors. Env is a uniquely flexible molecular machine, and deep understanding of its immunogenicity and susceptibility to inhibition requires an appreciation of its atomically resolved conformational dynamics. Structural studies using truncated, solubilized, and stabilized Env constructs have yielded detailed atomic models of its main open and closed conformational states. Emerging structural studies of full-length Env support identification of asymmetric closed conformations as the “default intermediate state” (DIS), revealing details of a potentially pivotal role of quaternary asymmetry in Env conformational dynamics. At the same time, both single-molecule FRET (smFRET) and crosslinking mass spectrometry (XL-MS) of Env suggest the existence of at least one, sometimes dominant conformational state that has not been structurally characterized. This “State-1” conformation nonetheless seems relevant for both immune recognition and susceptibility to small-molecule inhibitors. We will leverage advanced Molecular Dynamics (MD) methods including targeted MD, temperature-accelerated MD, and string method to provide atomic level models for the opening of HIV-1 Env from closed (State 2) to open (State 3) conformational states and to identify critical structural changes separating State-2 from the poorly understood State-1 Env. The MD simulation methods we use will incorporate biases from multi-perspective smFRET and XL-MS, and they will in turn provide direction for expanding the set of Env constructs used in those experiments, establishing an iterative approach that progressively better defines transition mechanisms and State 1. An atomic-level understanding of HIV-1 Env conformational dynamics, identification of a yet to be structurally characterized pre-triggered conformational states, as well as the mechanism of Env activation for fusion will inform immunogen design and antiviral therapies.


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 = $790,210 )
2025	2025	DREXEL UNIVERSITY	3141 CHESTNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	3	8/8/2025	NON-COMPETING CONTINUATION	$790,210
														Subtotal = $790,210

Issue Date FY: 2024 ( Subtotal = $797,785 )
2024	2024	DREXEL UNIVERSITY	3141 CHESTNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	2	6/26/2024	NON-COMPETING CONTINUATION	$797,785
														Subtotal = $797,785

Issue Date FY: 2023 ( Subtotal = $825,050 )
2023	2023	DREXEL UNIVERSITY	3141 CHESTNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	1	7/10/2023	NEW	$825,050
														Subtotal = $825,050

Grand Total All Awards = $2,413,045

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Combining Molecular Simulations and Biophysical Methods to Characterize Conformational Dynamics of the HIV-1 Envelope Glycoprotein

Award Number: R01AI178833

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/10/2023

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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