Computational and Theoretical Studies of Retroviral Replication - Resubmission

逆转录病毒复制的计算和理论研究 - 重新提交

• 批准号: 9910613
• 负责人: Alvin Yu
• 金额: $ 6.49万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9910613
• 关键词: Adopted; Anti-Retroviral Agents; Antiviral Therapy; Arginine; Binding; Biochemical; Biology; Biophysical Process; Biophysics; Capsid; Capsid Proteins; Cells; Cellular biology; Charge; Chemicals; Collaborations; Computer Simulation; Computing Methodologies; Cryo-electron tomography; Cryoelectron Microscopy; Crystallization; Cytoplasm; DNA Integration; Data; Defect; Development; Elements; Event; Genetic Materials; Genetic Polymorphism; Genome; Goals; Grain; Growth; HIV; HIV Infections; HIV-1; Immune; Infection; Innate Immune Response; Investigation; Knowledge; Lead; Length; Life Cycle Stages; Link; Macaca mulatta; Mechanics; Methods; Modeling; Molecular; Molecular Conformation; Morphology; Nature; Nucleotides; Pattern; Physics; Phytic Acid; Polyproteins; Positioning Attribute; Process; Proteins; Protons; Replication-Associated Process; Research; Resolution; Retroviridae; Role; Statistical Mechanics; Structural Biologist; Structure; Suggestion; Surface; System; TRIM Gene; Theoretical Studies; Thermodynamics; Time; Validation; Viral; Viral Physiology; Viral Reverse Transcription; Virion; Virus; Virus Integration; Virus Replication; Work; chemical bond; combat; computer studies; design; flexibility; gag Gene Products; improved; insight; molecular dynamics; molecular scale; novel; novel therapeutic intervention; particle; physical property; protonation; quantum chemistry; self assembly; sensor; simulation; structural biology; three dimensional structure; trafficking; viral DNA; viral RNA; virology

PROJECT SUMMARY Retroviral replication relies on atomic-scale phenomena such as the quantum chemistry of bond formation and large scale processes such as protein self-assembly. These processes are fundamentally multiscale in nature, since they span time and length scales from the molecular to the mesoscopic. For instance, during viral particle maturation, proteolytic cleavage of the group specific antigen polyprotein (Gag) releases capsid (CA) proteins, which are subsequently reassembled into a conical capsid. Our long-term goal is to develop and apply novel multiscale computational approaches to study retroviral replication. To achieve this goal, there are two main foci. The first focus is to develop multiscale simulation methods for which there are two separate strategies. (1) Strategies that link atomic-level structures and simulations to lower resolution models using rigorous statistical mechanical approaches or so-called “bottom-up” coarse-graining methods. (2) Strategies that use experimental data to directly develop coarse models, which are subsequently refined at higher resolutions. These are “top-down” approaches. The second focus is to apply these methods to uncover the mechanisms by which key proteins might influence retroviral replication. This proposal will concentrate on three biomolecular systems to probe the viral replication process: the innate immune sensors, TRIM5α, that recognize and destroy viral capsids, the CA protein that encases the viral DNA, and CA hexamers that form pores in the capsid. Investigations into the biophysical mechanisms involved will be guided by three specific aims (1) to determine how TRIM5α nucleate and grow protein lattices that encage capsids, (2) to identify the origins for capsid polymorphism, and (3) to investigate chemical features of capsid pores that contribute to capsid stability or viral function. Top-down coarse-grained models of TRIM5α and CA proteins will be developed and made more physically accurate using available experimental, structural, and biochemical data. Bottom-up coarse-grained models for CA will be constructed using atomistic simulations of viral capsids. Microsecond timescale atomistic simulations of CA hexamers capsid pores will also be performed to lay the groundwork for reactive molecular dynamics simulations approaches that allow for proton transport and chemical bond formation. A key approach, at all stages of our studies, is to develop multiscale computational methods that couple each level of description to the next. Our computational predictions on retroviral mechanism will be validated and/or refined in collaboration with three leading experimentalists. Collectively, insights from these studies will broadly impact the fields of molecular simulation, virology, and biophysics. Findings from these studies have the potential to aid in the development of new therapeutic strategies to combat retroviral infection.

项目摘要 逆转录病毒复制依赖于原子尺度的现象，如键形成的量子化学， 大规模的过程，如蛋白质自组装。这些过程本质上是多尺度的， 因为它们跨越了从分子到介观的时间和长度尺度。例如，在病毒颗粒 成熟，组特异性抗原多蛋白（Gag）的蛋白水解裂解释放衣壳（CA）蛋白， 其随后重新组装成圆锥形衣壳。我们的长期目标是开发和应用新的 多尺度计算方法来研究逆转录病毒复制。 为了实现这一目标，有两个主要重点。第一个重点是开发多尺度模拟方法， 有两种不同的策略。(1)将原子级结构和模拟链接到更低 分辨率模型使用严格的统计机械方法或所谓的“自下而上”粗粒度 方法. (2)使用实验数据直接开发粗略模型的策略，随后 以更高的分辨率进行优化。这些是“自上而下”的方法。第二个重点是应用这些方法 以揭示关键蛋白质可能影响逆转录病毒复制的机制。 这项建议将集中在三个生物分子系统来探测病毒的复制过程： 免疫传感器TRIM 5 α，识别并破坏病毒衣壳，即包裹病毒DNA的CA蛋白， 和在衣壳中形成孔的CA六聚体。对所涉及的生物物理机制的调查将 受三个具体目标的指导：（1）确定TRIM 5 α如何成核和生长蛋白质晶格， （2）确定衣壳多态性的起源，（3）研究衣壳的化学特征， 有助于衣壳稳定性或病毒功能的孔。TRIM 5 α和CA的自顶向下粗粒度模型 蛋白质将被开发，并利用现有的实验，结构， 生化数据。自下而上的CA粗粒度模型将使用原子模拟来构建， 病毒衣壳CA六聚体衣壳孔的微秒时间尺度原子模拟也将在 为反应分子动力学模拟方法奠定了基础，该方法允许质子 运输和化学键的形成。在我们研究的所有阶段，一个关键的方法是开发多尺度 将每一级描述与下一级描述相结合的计算方法。 我们对逆转录病毒机制的计算预测将与以下合作进行验证和/或改进： 三位顶尖的实验家总的来说，这些研究的见解将广泛影响以下领域： 分子模拟、病毒学和生物物理学。这些研究的结果有可能有助于 制定新的治疗策略，以对抗逆转录病毒感染。