Multiscale modeling of supramolecular protein-DNA assemblies

超分子蛋白质-DNA 组装体的多尺度建模

• 批准号: 8327188
• 负责人: Michael Feig
• 金额: $ 28.44万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-24 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8327188
• 关键词: Address; Biological Assay; Biological Process; Biology; Cell physiology; Cereals; Characteristics; Complex; Computer Simulation; Computing Methodologies; DNA; DNA Repair; DNA Repair Gene; DNA biosynthesis; DNA-Directed RNA Polymerase; Development; Disease; Gene Expression; Genetic Transcription; Goals; Learning; MSH2 gene; MSH6 gene; Malignant Neoplasms; Methodology; Methods; Mismatch Repair; Modeling; Molecular; Molecular Biology; Molecular Conformation; Nature; Nucleic Acids; Nucleotides; Phase; Play; Process; Property; Protein Complex Subunit; Protein Dynamics; Protein translocation; Proteins; RNA; RNA Polymerase II; Research; Resolution; Ribosomes; Role; Scanning; Scheme; Signal Transduction; Slide; Structure; System; Systems Biology; Time; Transcription Process; Yeasts; base; computer studies; innovation; insight; molecular dynamics; multi-scale modeling; mutant; novel; public health relevance; repaired; research study; simulation; structural biology

DESCRIPTION (provided by applicant): Novel coarse-graining and multiscale simulation methods are developed and applied in mechanistic studies of supramolecular protein-nucleic acid assemblies. The coarse-grained model relies on an intermediate- resolution model that preserves quasi-atomistic resolution and gains transferability from a physically- motivated all-atom force field like interaction potential. A multiscale modeling scheme is proposed where a biomolecular system is represented with a mixed coarse-grained/all-atom representation. Applications focus on DNA mismatch recognition and initiation of repair by bacterial MutS and eukaryotic MSH2-MSH6 as well as transcription by yeast RNA polymerase II. Both systems involve complex dynamic interactions of multi- subunit protein complexes with nucleic acids that will be addressed with a combination of unbiased and biased simulations at both the all-atom and coarse-grained levels. Biophysical insight will consist of specific mechanistic and energetic aspects of the mismatch recognition process in MutS/MSH2-MSH6 and the elongation phase in RNA polymerase II but also provide a more general understanding of translocation of proteins along nucleic acids which plays a crucial role in many protein-nucleic acid interactions. Computational studies of RNA polymerase II will be validated through experimental characterization of RNA polymerase II mutants with predicted altered functional properties. 1 PUBLIC HEALTH RELEVANCE: Computer simulations based on novel methodology are used to study the structure and dynamics of protein- nucleic acid complexes. Molecular complexes involved in repair of damaged DNA and in the transcription from DNA to RNA are studied to gain detailed mechanistic insight into fundamental biology and processes related to disease, in particular cancer. Experiments are carried out to validate computational predictions for the transcription process. 1

描述（由申请人提供）：开发了新颖的粗粒度和多尺度模拟方法，并将其应用于超分子蛋白质-核酸组装体的机理研究。粗粒度模型依赖于中间分辨率模型，该模型保留准原子分辨率并从物理驱动的全原子力场（如相互作用势）获得可转移性。提出了一种多尺度建模方案，其中生物分子系统用混合的粗粒度/全原子表示来表示。应用重点是细菌 MutS 和真核 MSH2-MSH6 的 DNA 错配识别和启动修复以及酵母 RNA 聚合酶 II 的转录。这两个系统都涉及多亚基蛋白质复合物与核酸的复杂动态相互作用，这些相互作用将通过全原子和粗粒度水平上的无偏和有偏模拟的组合来解决。生物物理学见解将包括 MutS/MSH2-MSH6 中的错配识别过程和 RNA 聚合酶 II 中的延伸阶段的特定机制和能量方面，而且还提供对蛋白质沿核酸易位的更一般的理解，这在许多蛋白质-核酸相互作用中发挥着至关重要的作用。 RNA 聚合酶 II 的计算研究将通过对具有预测的功能特性改变的 RNA 聚合酶 II 突变体的实验表征进行验证。 1 公共健康相关性：基于新方法的计算机模拟用于研究蛋白质-核酸复合物的结构和动力学。研究参与受损 DNA 修复和从 DNA 转录为 RNA 的分子复合物，以获得对基础生物学和与疾病（特别是癌症）相关过程的详细机制了解。进行实验以验证转录过程的计算预测。 1