CDI-Type I Collaborative Research: Multi-Scale Modeling of Protein-Modulated DNA Large-Scale Dynamics by Free Energy Surface Matching

CDI-I 型合作研究：通过自由能表面匹配对蛋白质调节 DNA 大规模动力学进行多尺度建模

• 批准号: 0941470
• 负责人: Noel Perkins
• 金额: $ 35.66万
• 依托单位: Regents of the University of Michigan - Ann Arbor
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0941470&HistoricalAwards=false
• 关键词: CDI; Type; Collaborative; Research; Multi

Protein-DNA interactions govern essentially all major genetic transactions within the cell including, for example, DNA replication, repair, transcription and recombination. These actions, which begin locally at the nm-sized site of protein-DNA binding, often generate very large, ?Ým-scale DNA conformational changes. The enormously broad length and time scales invoked in these complex dynamical systems create formidable challenges for computational modeling. This project addresses this challenge by proposing a transformative, multi-scale computational method that captures the time-evolution of large protein-DNA complexes on biologically relevant length/time scales (e.g., micron/millisecond and longer). Our method begins with (one-time) massively parallel MD computations and umbrella sampling of the protein domain to establish an unperturbed free energy surface in the presence of a short (atomically-detailed) fragment of the DNA duplex. Next, we couple a rod model of the long DNA duplex to the protein (by geometric protein boundary conditions) and form a reduced-order dynamical system (Fokker-Planck probability) model of the entire protein-DNA complex for the dominant degrees of freedom. The resulting Fokker-Plank model captures the complete (two-way) dynamic coupling of the rod/DNA and protein domains and enables integration over the desired long length/time scales. We illustrate our method on two large and challenging systems; namely 1) the relaxation of DNA supercoils by human topoisomerase I, and 2) the packing and ejection of dsDNA from viral capsids in bacteriophages.This research aims at long standing challenges in predicting the dynamical behavior of large biomolecular systems on long length and time scales. These predictions are essential for understanding fundamental cellular processes (including DNA transcription, replication, and repair) and interpreting exciting results from single molecule experiments. More broadly, our method provides a systematic means to couple atomistic to continuum level (e.g. micron-scale) descriptions of matter in a wide range of fields. Other fields may include DNA/RNA complexes that form large scale nucleic acid (origami) structures for scaffolding, computing, or nanopropelling; carbon nanotubes interacting with organic and inorganic nanoparticles; nanowires and their use for bio-molecular detection; and the structural dynamics of flagella, collagen fibers and cellular cytoskeleton elements (e.g., actin, neurofilaments, microtubules), among others.

蛋白-DNA相互作用基本上控制了细胞内的所有主要遗传交易，包括例如DNA复制，修复，转录和重组。这些动作始于蛋白质-DNA结合的NM大小位点，通常会产生非常大的，尺度的DNA构象变化。在这些复杂的动态系统中调用的巨大长度和时间尺度为计算建模带来了巨大的挑战。该项目通过提出一种变革性的多尺度计算方法来解决这一挑战，该方法捕获了大型蛋白-DNA复合物在生物相关的长度/时间尺度上（例如，微米/毫秒及更长）的时间进化。我们的方法始于（一次性）（一次性）平行的MD计算和蛋白质结构域的伞采样，以在存在DNA双链体的短（原子详细）片段的情况下建立不受干扰的自由能表面。接下来，我们将长DNA双链体的杆模型与蛋白质（通过几何蛋白质边界条件）相结合，并形成了整个蛋白DNA复合物的降低阶动力系统（Fokker-Planck概率）模型，以实现自由度的主要自由度。所得的fokker-Plank模型捕获了杆/DNA和蛋白质结构域的完整（双向）动态耦合，并在所需的长度/时间尺度上启用积分。我们在两个大型挑战系统上说明了我们的方法；即1）人拓扑异构酶I和2）细菌中病毒capsids dsDNA的填料和弹药的放松。这项研究旨在预测长长和时间尺度上大分子系统的大型生物分子系统的动态行为。这些预测对于理解基本细胞过程（包括DNA转录，复制和修复）以及解释单分子实验的令人兴奋的结果至关重要。更广泛地说，我们的方法提供了一种系统的手段，可以将原子化以继续在各个领域中继续对物质的描述（例如微米级描述）。其他领域可能包括形成大规模核酸（折纸）结构的DNA/RNA复合物，用于脚手架，计算或纳米丙烯酸；碳纳米管与有机和无机纳米颗粒相互作用；纳米线及其用于生物分子检测的使用；以及鞭毛，胶原纤维和细胞细胞骨架元件的结构动力学（例如肌动蛋白，神经丝，微管）等。