Monday, September 15, 2025 9/15/2025

The role of conformational dynamics of enveloped virus spike proteins in cell entry

Award Number: R35GM151169
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: 09/01/2023
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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The role of conformational dynamics of enveloped virus spike proteins in cell entry - Research Abstract: The spike/fusion glycoproteins residing on the surface of human enveloped viruses are targets of immune response and are the focus of researchers developing vaccines and antiviral treatments. The conformational dynamics of spike proteins drive the entry of enveloped viruses into cells via viral membrane fusion and facilitate antibody recognition. However, the lack of deep insights into dynamics has prevented a complete elucidation of the molecular mechanism by which spike proteins promote virus entry. Many viruses, such as coronavirus SARS-CoV-2, respiratory syncytial virus (RSV), and HIV-1, share a similar viral fusion mechanism (type-I) mediated by their respective spike proteins. These spikes undergo dramatic structural changes, and the energy released from conformational transitions overcomes the fusion kinetic barriers. However, our understanding of the multi-step fusion process mainly relies on individual structural snapshots of spike proteins at fusion endpoints. How these endpoints are correlated in a time-resolved manner and the order and frequency of conformational events underlying virus entry remain largely elusive. The proposed research extends our efforts to explore viral membrane fusion and is supported by our experience probing the conformational dynamics of the SARS-CoV-2 spike (S) and HIV-1 envelope (Env) glycoproteins. The overarching goal of this project is to integrate our knowledge into a generic working model that will describe a time-resolved stepwise framework of the type-I fusion mechanism, in which the conformational trajectories of fusion proteins are explicitly defined in space and time. We pioneered the use of the single-molecule Förster resonance energy transfer (smFRET) to study S and revealed multiple S conformations on the virus. We delineated sequential transitions of S from closed to open conformations upon activation by cellular receptors. We provided the first experimental evidence of decelerated transition dynamics from open states, suggesting increased stability of the fusion-reactive open state to be part of the SARS-CoV-2 adaption strategies. Here, we will use an integrated platform of smFRET and virus-to-cell fusion in combination with computational and structural tools to reveal the conformational plasticity S adapts during virus evolution and to visualize the conformational trajectory S undergoes during fusion. We will perform comparative studies on another respiratory virus - RSV fusion (F) protein, with interest in other type-I spike proteins of newly emerging viruses. We will elucidate conformational events and transition dynamics of F-mediated viral membrane fusion and evaluate whether conformation- presentation of F-based vaccine candidates represents the predominant state exposed to the host. The studies are expected to allow us to identify the common and divergent traits of the S- and F-mediated fusion processes that will advance our knowledge and help us define the common theme of the type-I fusion mechanism. We envision that this program of research using different advanced technologies will reveal unrecognized insights into virus entry that lay the foundation for advances in anti-viral interventions, in line with the mission of NIGMS.


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 = $372,500 )
2025	2025	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT TYLER	11937 US HIGHWAY 271	TYLER	TX	75708	SMITH	USA	Biomedical Research and Research Training	000	3	8/7/2025	NON-COMPETING CONTINUATION	$372,500
														Subtotal = $372,500

Issue Date FY: 2024 ( Subtotal = $372,500 )
2024	2024	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT TYLER	11937 US HIGHWAY 271	TYLER	TX	75708	SMITH	USA	Biomedical Research and Research Training	000	2	8/16/2024	NON-COMPETING CONTINUATION	$372,500
														Subtotal = $372,500

Issue Date FY: 2023 ( Subtotal = $372,500 )
2023	2023	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT TYLER, THE	11937 US HWY 271	TYLER	TX	75708	SMITH	USA	Biomedical Research and Research Training	000	1	8/24/2023	NEW	$372,500
														Subtotal = $372,500

Grand Total All Awards = $1,117,500

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The role of conformational dynamics of enveloped virus spike proteins in cell entry

Award Number: R35GM151169

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: 09/01/2023

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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