Multiscale modeling of supramolecular protein-DNA assemblies

描述（由申请人提供）：开发了新的粗粒化和多尺度模拟方法，并将其应用于超分子蛋白质-核酸组装体的机理研究。粗粒度模型依赖于一个中间分辨率模型，该模型保留了准原子分辨率，并从物理激励的全原子力场（如相互作用势）获得了可转移性。提出了一种多尺度建模方案，其中生物分子系统用混合粗粒度/全原子表示来表示。应用集中在DNA错配识别和启动修复的细菌MutS和真核MSH2-MSH6以及转录酵母RNA聚合酶II。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，这将在全原子和粗粒度水平上用无偏和有偏模拟的组合来解决。生物物理学的见解将包括特定的机制和能量方面的错配识别过程中MutS/MSH2-MSH6和RNA聚合酶II的延伸阶段，但也提供了一个更一般的理解蛋白质的易位沿着核酸在许多蛋白质-核酸相互作用中发挥着至关重要的作用。RNA聚合酶II的计算研究将通过预测改变功能特性的RNA聚合酶II突变体的实验表征进行验证。1 公共卫生相关性：基于新方法学的计算机模拟被用于研究蛋白质-核酸复合物的结构和动力学。参与修复受损DNA和从DNA到RNA的转录的分子复合物被研究，以获得与疾病，特别是癌症相关的基础生物学和过程的详细机制见解。进行实验，以验证转录过程的计算预测。1

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