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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

基本信息

批准号：
10341163
负责人：
Alvin Yu
金额：
$ 1.54万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10341163
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

项目摘要

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.

项目概要逆转录病毒复制依赖于原子尺度的现象，例如键形成的量子化学和大规模过程，例如蛋白质自组装。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，在病毒颗粒期间成熟，组特异性抗原多蛋白 (Gag) 的蛋白水解裂解释放衣壳 (CA) 蛋白，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颖的研究逆转录病毒复制的多尺度计算方法。为实现这一目标，主要有两个重点。第一个重点是开发多尺度模拟方法其中有两个单独的策略。 (1) 将原子级结构和模拟与较低层次联系起来的策略使用严格的统计机械方法或所谓的“自下而上”粗粒度的分辨率模型方法。 (2)利用实验数据直接开发粗模型并随后进行的策略以更高的分辨率进行细化。这些是“自上而下”的方法。第二个重点是应用这些方法揭示关键蛋白质可能影响逆转录病毒复制的机制。该提案将集中于三个生物分子系统来探测病毒复制过程：先天的免疫传感器 TRIM5α，可识别并破坏病毒衣壳，即包裹病毒 DNA 的 CA 蛋白，和 CA 六聚体，在衣壳中形成孔。对所涉及的生物物理机制的研究将以三个具体目标为指导 (1) 确定 TRIM5α 如何成核和生长蛋白质晶格，以容纳衣壳，(2) 鉴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。 TRIM5α 和 CA 自上而下的粗粒度模型使用现有的实验、结构和技术，将开发蛋白质并使其在物理上更加精确。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为反应分子动力学模拟方法奠定基础，该方法允许质子运输和化学键的形成。在我们研究的各个阶段，一个关键方法是开发多尺度将每个描述级别与下一个描述级别相结合的计算方法。我们对逆转录病毒机制的计算预测将与以下机构合作进行验证和/或完善：三位领先的实验家。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开发新的治疗策略来对抗逆转录病毒感染。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Stability and molecular pathways to the formation of spin defects in silicon carbide.

DOI：
10.1038/s41467-021-26419-0
发表时间：
2021-11-03
期刊：
Nature communications
影响因子：
16.6
作者：
Lee EMY;Yu A;de Pablo JJ;Galli G
通讯作者：
Galli G

Cooperative multivalent receptor binding promotes exposure of the SARS-CoV-2 fusion machinery core.

DOI：
10.1038/s41467-022-28654-5
发表时间：
2022-02-22
期刊：
Nature communications
影响因子：
16.6
作者：
Pak AJ;Yu A;Ke Z;Briggs JAG;Voth GA
通讯作者：
Voth GA

Integrin-based mechanosensing through conformational deformation.

通过构象变形进行基于整合素的机械传感。

DOI：
10.1016/j.bpj.2021.09.010
发表时间：
2021
期刊：
Biophysical journal
影响因子：
3.4
作者：
Driscoll,TristanP;Bidone,TamaraC;Ahn,SangJoon;Yu,Alvin;Groisman,Alexander;Voth,GregoryA;Schwartz,MartinA
通讯作者：
Schwartz,MartinA

A Multiscale Coarse-grained Model of the SARS-CoV-2 Virion.

SARS-CoV-2 病毒粒子的多尺度粗粒度模型。

DOI：
10.1101/2020.10.02.323915
发表时间：
2020
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Yu,Alvin;Pak,AlexanderJ;He,Peng;Monje-Galvan,Viviana;Casalino,Lorenzo;Gaieb,Zied;Dommer,AbigailC;Amaro,RommieE;Voth,GregoryA
通讯作者：
Voth,GregoryA

Temperature and Phase Transferable Bottom-up Coarse-Grained Models.