CDI-Type 1 Collaborative Research: Multi-scale Modeling of Protein-Modulated DNA Large-Scale Dynamics by Free Energy Surface Matching

蛋白质-DNA相互作用基本上控制着细胞内所有主要的遗传过程，包括DNA的复制、修复、转录和重组。这些作用开始于蛋白质-DNA结合的nm大小的位点，通常产生非常大的m尺度DNA构象变化。在这些复杂的动力系统中调用的极大的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，该方法在生物学相关的长度/时间尺度上捕获大型蛋白质-DNA复合物的时间演化（例如，微米/毫秒和更长）。我们的方法开始于（一次性）大规模并行MD计算和伞形采样的蛋白质结构域，以建立一个未受干扰的自由能表面结合DNA的情况下。 接下来，我们将长DNA的杆模型耦合到蛋白质（通过几何蛋白质边界条件），并形成整个蛋白质-DNA复合物的降阶动力学系统（福克-普朗克概率）模型的主导自由度。由此产生的Fokker-Plank模型捕获了杆/DNA和蛋白质结构域的完整（双向）动态偶联，并能够在所需的长长度/时间尺度上进行整合。 我们用两个大的具有挑战性的系统来说明我们的方法，即1）人类拓扑异构酶I对DNA超螺旋的松弛，以及2）噬菌体中病毒衣壳对dsDNA的包装和排出。这项研究旨在解决长期存在的挑战，即在长的长度和时间尺度上预测大型生物分子系统的动力学行为。 这些预测对于理解基本的细胞过程（包括DNA转录，复制和修复）和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个系统的手段，耦合原子的连续水平（例如微米尺度）的物质在广泛的领域的描述。其他领域可以包括形成用于支架、计算或纳米推进的大规模核酸（折纸）结构的DNA/RNA复合物;与有机和无机纳米颗粒相互作用的碳纳米管;纳米线及其用于生物分子检测的用途;以及鞭毛、胶原纤维和细胞骨架元件（例如，肌动蛋白、神经丝、微管）等。

Multi-Scale Modeling of Protein-Modulated DNA Large-Scale DynamicsBy Free Energy Surface MatchingProtein-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, m-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 absence of bound DNA. Next, we couple a rod model of long DNA 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.