Multiscale Simulation of HIV-1 Virion Release and Maturation

HIV-1 病毒粒子释放和成熟的多尺度模拟

• 批准号: 10750700
• 负责人: Gregory A. Voth
• 金额: $ 54.29万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-10 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10750700
• 关键词: Address; Anions; Binding; Biological; Capsid; Cell membrane; Cell physiology; Cells; Collaborations; Complex; Computer Models; Computer Simulation; Crowding; Data; Development; Environment; Evolution; Freedom; Funding; Genome; Glycoproteins; Grain; Growth; Guide RNA; HIV Protease; HIV-1; HIV-1 protease; Hand; In Vitro; Infection; Investments; Kinetics; Knowledge; Letters; Life Cycle Stages; Link; Mediating; Membrane; Methodology; Methods; Modeling; Molecular; Morphology; Nucleic Acids; Pathway interactions; Physical condensation; Process; Property; Proteins; RNA; Research; Research Personnel; Resolution; Reverse Transcription; Ribonucleoproteins; Role; Site; Structure; Viral; Viral Genome; Viral Proteins; Virion; Virus; Virus Assembly; Work; atomic interactions; biophysical techniques; experimental study; gag Gene Products; in vivo; innovation; insight; model development; molecular dynamics; molecular modeling; molecular scale; novel; novel therapeutic intervention; particle; protein complex; recruit; self assembly; simulation; tool; virology

PROJECT SUMMARY Certain key processes in the HIV-1 viral lifecycle are still poorly or incompletely understood. These processes include the release of the virion from infected cells, the virion maturation, and the genome packaging within the virion as it matures. These processes are highly complex, involving sequential multiprotein and nucleic acid assembly and disassembly, as well as protein-mediated membrane interactions. Computationally simulating these processes thus requires the use of both all-atom (AA) and coarse-grained (CG) molecular dynamics (MD) methods in an innovative multiscale fashion in order to access the relevant spatial and temporal scales. The Voth group will develop and carry out both AA and CG simulations to study the large viral protein complexes relevant to these important problems in the HIV-1 life cycle. The specific processes to be studied are involved in the viral release and maturation processes, specifically the proteolytic cleavage of Gag and capsid assembly within the virion (Aim 1), the virion component reorganization and ribonucleoprotein complex condensation upon maturation (Aim 2), and the latter stage dynamics of virion release from infected cells (Aim 3). The computational model development and multiscale simulation efforts will be integrated and iterated with the experimental studies of two leading experimental investigators (John Briggs and Hans-Georg Kräusslich) and one independently funded collaborator (James Hurley). These novel and powerful multiscale computer simulations – and the collaborative effort with experimentalists – will provide new insight into the dynamical aspects of HIV-1 release and maturation which are not readily accessible to the experimental (or computational) efforts alone.

项目概要 HIV-1 病毒生命周期中的某些关键过程仍然知之甚少或不完全。 包括病毒体从受感染细胞中的释放、病毒体的成熟以及基因组内的包装 病毒体成熟时的这些过程非常复杂，涉及连续的多蛋白和核酸。 组装和拆卸，以及蛋白质介导的膜相互作用。 因此，这些过程需要使用全原子 (AA) 和粗粒度 (CG) 分子动力学 (MD) 以创新的多尺度方式方法，以便访问相关的空间和时间尺度。 Voth 小组将开发并进行 AA 和 CG 模拟来研究大型病毒蛋白复合物 与HIV-1生命周期中的这些重要问题相关的具体过程都涉及到。 在病毒释放和成熟过程中，特别是 Gag 和衣壳组装的蛋白水解切割 在病毒粒子内（目标 1），病毒粒子成分重组和核糖核蛋白复合物凝结在 成熟（目标 2），以及受感染细胞释放病毒颗粒的后期动态（目标 3）。 模型开发和多尺度模拟工作将与实验研究相结合和迭代 两位主要实验研究者（John Briggs 和 Hans-Georg Krausslich）和一位独立实验研究者 资助的合作者（詹姆斯·赫尔利）。这些新颖而强大的多尺度计算机模拟 - 以及 与实验者的合作——将为 HIV-1 释放的动态方面提供新的见解 和成熟度仅靠实验（或计算）努力是不容易实现的。