Project 1 - Molecular Dynamics of HIV-1 Entry: Visualizing Transient Intermediates
项目 1 - HIV-1 进入的分子动力学:可视化瞬时中间体
基本信息
- 批准号:10506667
- 负责人:
- 金额:$ 31.54万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-06-14 至 2027-03-31
- 项目状态:未结题
- 来源:
- 关键词:AIDS/HIV problemAutomobile DrivingBioinformaticsBiophysicsCellsComplexComputational BiologyCoupledCouplingCryoelectron MicroscopyElementsEnsureEventEvolutionGoalsHIVHIV Envelope Protein gp120HIV-1HIV-1 vaccineHydrophobicityImmune systemInfectionInvestigationKineticsLocationMediatingMembraneMethodsMolecularMolecular ConformationMovementMutationPathway interactionsPeptidesPersonsPositioning AttributeProcessPublishingResearchResolutionRoentgen RaysSamplingSiteStructureSurfaceThermodynamicsTimeTryptophanVaccinesVirusbaseconformational conversiondesigndrug developmentenv Gene Productsexpectationexperimental studyextracellular vesiclesmolecular dynamicsmulti-scale modelingnovelpreventreceptorsimulationstructural biologytemperature jumptemporal measurementtoolvaccine development
项目摘要
Abstract – Project 1
Approximately 40 million people worldwide are living with HIV/AIDS; however, a protective vaccine or functional
cure remain elusive despite four decades of intense research. HIV-1 evades the immune system through its
rapid structural evolution during infection and replication, and the implications of these structural changes in the
HIV-1 Envelope (Env) protein on HIV-1 fusion and entry into cells is not completely understood. Our overall goal
in this project is to define the steps leading to formation of the so called pre-hairpin intermediate of the HIV-1
Env to its decay into later fusion intermediates. Initiation of this event is typically described as a ‘harpoon-like”
insertion of the FP into the host membrane. While this depiction is illustrative of the earliest anchoring event, it
is not physically descriptive. The inherent instability of the pre-hairpin intermediate has rendered observation of
its structure intractable. In this project, we aim to combine advances in molecular simulation with cutting-edge
experimental methods to interrogate this process at high spatial and temporal resolution. To accomplish these
aims, Project 1 will leverage expertise in the structural biology and computational biology cores to develop and
apply methods to this problem.
Our long-term goal is to develop a complete, time resolved and atomically detailed mechanism of HIV-1 Env
fusion. The overall objective for this project is to develop and apply new methods in computational and structural
biology to make possible the interrogation of rare transient states along the fusion pathway. The specific targets
in this proposal are (i) to determine the conformational transitions that trigger fusion peptide release from its
association with the Env trimer, (ii) to examine passage of the fusion peptide from its trimeric anchor to the host
membrane surface, (iii) to identify the determinants of fusion peptide insertion, assembly, and anchoring in the
host membrane, and iv) to delineate the conformational transitions that facilitate gp120 shedding from gp41. The
central hypothesis driving this study is that each transition is tightly regulated, displaying sequential, cooperative
control at each stage. The rationale for this project is that advanced, multiscale modelling of this process
combined with cutting edge structural biology tools can elucidate the mechanism by which transitions at this
intermediate stage of entry are regulated.
Upon completion of these aims, we expect to provide kinetically resolved, atomic-level dynamics understanding
of HIV-1 Env fusion peptide triggering, release, and membrane engagement. These results will have broad
impact on HIV-1 vaccine and drug development specifically and on virus entry investigations generally.
摘要-项目1
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Rory Henderson其他文献
Rory Henderson的其他文献
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{{ truncateString('Rory Henderson', 18)}}的其他基金
Project 1 - Molecular Dynamics of HIV-1 Entry: Visualizing Transient Intermediates
项目 1 - HIV-1 进入的分子动力学:可视化瞬时中间体
- 批准号:
10643917 - 财政年份:2022
- 资助金额:
$ 31.54万 - 项目类别:
Assessing HIV-1 Broadly Neutralizing Antibody Association Pathways for Vaccine Immunogen Design
评估疫苗免疫原设计的 HIV-1 广泛中和抗体关联途径
- 批准号:
10458681 - 财政年份:2021
- 资助金额:
$ 31.54万 - 项目类别:
Assessing HIV-1 Broadly Neutralizing Antibody Association Pathways for Vaccine Immunogen Design
评估疫苗免疫原设计的 HIV-1 广泛中和抗体关联途径
- 批准号:
10670990 - 财政年份:2021
- 资助金额:
$ 31.54万 - 项目类别:
Project 4: Computational panbetaCoV immunogen design
项目4:计算panbetaCoV免疫原设计
- 批准号:
10842505 - 财政年份:2021
- 资助金额:
$ 31.54万 - 项目类别:
Project 4: Computational panbetaCoV immunogen design
项目4:计算panbetaCoV免疫原设计
- 批准号:
10327526 - 财政年份:2021
- 资助金额:
$ 31.54万 - 项目类别:
Assessing HIV-1 Broadly Neutralizing Antibody Association Pathways for Vaccine Immunogen Design
评估疫苗免疫原设计的 HIV-1 广泛中和抗体关联途径
- 批准号:
10295287 - 财政年份:2021
- 资助金额:
$ 31.54万 - 项目类别:
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