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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要 HIV-1病毒生命周期中的某些关键过程仍然很差或不完全理解。这些过程包括从受感染细胞中释放病毒粒子，病毒体的成熟和基因组包装随着它的成熟。这些过程高度复杂，涉及顺序多蛋白和核酸组装和拆卸，以及蛋白质介导的膜相互作用。计算模拟因此，这些过程需要使用全原子（AA）和粗粒（CG）分子动力学（MD）以创新的多尺度方式使用相关的空间和临时量表的方法。这 Voth组将开发和进行AA和CG模拟，以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有关。涉及要研究的特定过程在病毒释放和成熟过程中，特别是GAG和衣壳组件的蛋白水解裂解在病毒体中（AIM 1），病毒体成分的重组和核糖核蛋白复合物在成熟（AIM 2），以及从感染细胞释放病毒粒子的后期动力学（AIM 3）。计算模型开发和多尺度模拟工作将被整合并迭代与实验研究两名领先的实验研究者（John Briggs和Hans-GeorgKräusslich）和一名独立的资助合作者（詹姆斯·赫利）。这些新颖而强大的多尺度计算机模拟 - 与实验者的合作努力 - 将为HIV-1发行的动态方面提供新的见解仅实验（或计算）工作不容易访问的成熟。