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: 7862767
• 负责人: Michael Feig
• 金额: $ 27.71万
• 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/7862767
• 关键词: Address; Biological Assay; Biological Process; Biology; Cell physiology; Cereals; Characteristics; Complex; Computer Simulation; Computing Methodologies; DNA; DNA Repair; DNA biosynthesis; DNA-Directed RNA Polymerase; Development; Disease; Gene Expression; Genetic Transcription; Goals; Learning; 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）：新型的粗粒和多尺度模拟方法是开发并应用于超分子蛋白核酸组件的机械研究。粗粒度模型依赖于中间分辨率模型，该模型可保留准原子分辨率并从物理动机的全原子力场（如相互作用电位）中获得可转移性。提出了一个多尺度建模方案，其中生物分子系统用混合的粗粒/全原子表示表示。应用于DNA不匹配的识别和通过细菌MUT和真核MSH2-MSH6以及酵母RNA聚合酶II转录的修复。这两种系统都涉及多亚基蛋白复合物与核酸的复杂动态相互作用，这些蛋白质复合物将与全原子和粗粒水平的无偏和偏置模拟的结合来解决。生物物理洞察力将由MUTS/MSH2-MSH6中错配识别过程的特定机械和能量方面组成，RNA聚合酶II中的伸长阶段，但也提供了沿核酸易位的易位的一般了解，在许多蛋白质核酸相互作用中起着至关重要的作用。 RNA聚合酶II的计算研究将通过对具有预测功能特性的RNA聚合酶II突变体的实验表征来验证。 1 公共卫生相关性：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。研究了与受损DNA修复以及从DNA到RNA的转录中有关的分子复合物，以获取有关与疾病（尤其是癌症）有关的基本生物学和过程的详细机械洞察力。进行实验以验证转录过程的计算预测。 1