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:10643917
- 负责人:
- 金额:$ 25.69万
- 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:AccelerationAutomobile DrivingBioinformaticsBiophysicsCellsComplexComputational BiologyCoupledCouplingCryoelectron MicroscopyElementsEnsureEventEvolutionGoalsHIVHIV Envelope Protein gp120HIV-1HIV-1 vaccineHIV/AIDSHydrophobicityImmune EvasionImmune systemInfectionInvestigationKineticsLocationMediatingMembraneMethodsMolecularMolecular ConformationMovementMutationPathway interactionsPeptidesPersonsPositioning AttributeProcessProteinsPublishingResearchResolutionRoentgen RaysSamplingSiteStructureSurfaceThermodynamicsTimeTryptophanVaccinesVirusVisualizationbaseconformational conversiondesigndrug developmentexpectationexperimental 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
全世界大约有 4000 万人感染艾滋病毒/艾滋病;然而,保护性疫苗或功能性疫苗
尽管经过四十年的深入研究,治愈方法仍然难以捉摸。 HIV-1通过其自身免疫系统逃避免疫系统
感染和复制过程中的快速结构进化,以及这些结构变化的影响
HIV-1 包膜 (Env) 蛋白对 HIV-1 融合和进入细胞的影响尚不完全清楚。我们的总体目标
该项目的目的是确定形成所谓的 HIV-1 发夹前中间体的步骤
Env 衰变成后来的融合中间体。该事件的启动通常被描述为“鱼叉状”
将 FP 插入宿主膜。虽然这个描述说明了最早的锚定事件,但它
不是物理描述性的。预发夹中间体固有的不稳定性使得观察到
其结构棘手。在这个项目中,我们的目标是将分子模拟的进步与尖端技术结合起来
以高空间和时间分辨率询问该过程的实验方法。为了完成这些
目标,项目 1 将利用结构生物学和计算生物学核心的专业知识来开发和
应用方法来解决这个问题。
我们的长期目标是开发一个完整的、时间分辨的、原子详细的 HIV-1 Env 机制
融合。该项目的总体目标是开发和应用计算和结构方面的新方法
生物学使沿着融合途径询问罕见的瞬态成为可能。具体目标
该提案的目的是 (i) 确定触发融合肽从其结构中释放的构象转变。
与 Env 三聚体结合,(ii) 检查融合肽从其三聚体锚定到宿主的通道
膜表面,(iii) 确定融合肽插入、组装和锚定的决定因素
宿主膜,和 iv) 描绘促进 gp120 从 gp41 脱落的构象转变。这
推动这项研究的中心假设是,每个转变都受到严格调控,表现出顺序性、协作性
每个阶段的控制。该项目的基本原理是对该过程进行先进的多尺度建模
与尖端的结构生物学工具相结合可以阐明这种转变的机制
进入的中间阶段受到监管。
完成这些目标后,我们期望提供动力学解析的原子级动力学理解
HIV-1 Env 融合肽的触发、释放和膜结合。这些成果将具有广泛的
具体对 HIV-1 疫苗和药物开发以及对病毒进入调查的总体影响。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Rory Henderson其他文献
Rory Henderson的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
10506667 - 财政年份:2022
- 资助金额:
$ 25.69万 - 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:
$ 25.69万 - 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:
$ 25.69万 - 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:
$ 25.69万 - 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:
$ 25.69万 - 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:
$ 25.69万 - 项目类别:
相似海外基金
Establishment of a method for evaluating automobile driving ability focusing on frontal lobe functions and its application to accident prediction
以额叶功能为中心的汽车驾驶能力评价方法的建立及其在事故预测中的应用
- 批准号:
20K07947 - 财政年份:2020
- 资助金额:
$ 25.69万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Evaluation of the Effectiveness of Multi-Professional Collaborative Assessment of Cognitive Function and Automobile Driving Skills and Comprehensive Support
认知功能与汽车驾驶技能多专业协同评估效果评价及综合支持
- 批准号:
17K19824 - 财政年份:2017
- 资助金额:
$ 25.69万 - 项目类别:
Grant-in-Aid for Challenging Research (Exploratory)
Development of Flexible Automobile Driving Interface for Disabled People
残疾人灵活汽车驾驶界面开发
- 批准号:
25330237 - 财政年份:2013
- 资助金额:
$ 25.69万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Automobile driving among older people with dementia: the effect of an intervention using a support manual for family caregivers
患有痴呆症的老年人的汽车驾驶:使用家庭护理人员支持手册进行干预的效果
- 批准号:
23591741 - 财政年份:2011
- 资助金额:
$ 25.69万 - 项目类别:
Grant-in-Aid for Scientific Research (C)














{{item.name}}会员




