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

蛋白质调控DNA大规模动力学的多尺度建模通过自由能表面匹配蛋白质-DNA相互作用基本上控制细胞内的所有主要遗传交易，例如，DNA复制、修复、转录和重组。这些作用开始于蛋白质-脱氧核糖核酸结合的纳米级位置，通常会产生非常大的、61549微米级的脱氧核糖核酸构象变化。在这些复杂的动力系统中调用的巨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应对这一挑战，该方法捕捉生物相关长度/时间尺度(例如微米/毫秒或更长)上大型蛋白质-DNA复合体的时间进化。我们的方法开始于(一次性)大规模并行MD计算和蛋白质结构域的伞形采样，以在没有结合DNA的情况下建立一个不受扰动的自由能表面。接下来，我们将长DNA的杆状模型(通过几何蛋白质边界条件)耦合到蛋白质上，形成整个蛋白质-DNA复合体的主要自由度的降阶动力学系统(Fokker-Planck概率)模型。由此产生的福克-普朗克模型捕捉到杆/DNA和蛋白质结构域的完全(双向)动态耦合，并能够在所需的长/时间尺度上进行整合。我们在两个具有挑战性的大系统上说明了我们的方法，即1)人类拓扑异构酶I对DNA超螺旋的松弛，以及2)在噬菌体中病毒衣壳中dsDNA的包装和排出。这项研究旨在预测大生物分子系统在长时间和长时间尺度上的动力学行为方面的长期挑战。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)和解释来自单分子实验的令人兴奋的结果是必不可少的。更广泛地说，我们的方法提供了一种系统的方法，将原子级到连续层级(例如微米级)的描述耦合到广泛领域的物质。其他领域可能包括形成用于支架、计算或纳米推进的大规模核酸(折纸)结构的DNA/RNA复合体；碳纳米管与有机和无机纳米颗粒的相互作用；纳米线及其在生物分子检测中的应用；鞭毛、胶原纤维和细胞细胞骨架元素(如肌动蛋白、神经细丝、微管)的结构动力学等。

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.