Mathematical Modeling of Biomolecule Translocation through Nanopores

描述（由申请人提供）：本提案的目标是建立一个基于连续体的数学模型，以获得设计使用纳米孔的无标签、低成本、高速和高通量DNA测序方法所需的基础知识。纳米孔正在成为第三代测序设备开发的一个有希望的候选者，它将满足美国国立卫生研究院设定的1000美元人类基因组测序范例的目标。在过去的十年中，已经收集了许多关于DNA分子通过纳米孔易位的实验数据，但是仍然缺乏一个简单的基于连续体的模型，该模型可以用统计术语描述易位过程，并且可以直接与实验观察到的集合平均进行比较。有限的现有分析连续统模型仍然不能完全解释实验观察。简单的物理论证表明，浓度极化和纳米孔的形状可能能够弥合实验结果与现有简单连续体模型的理论预测之间的系绳力或移位速度的差异。因此，具体目标是：(1)利用我们提出的基于连续体的数学模型探索浓度极化的作用；(2)通过数值模拟研究利用外部施加的盐浓度通过纳米孔调节DNA易位的可行性；(3)了解纳米孔不规则形状对DNA易位的影响。所提出的连续介质模型将确定更准确的易位速度与各种条件（如盐浓度、纳米孔尺寸、表面电荷和电场强度）之间的显式关系，并准备与大量现有实验数据进行直接比较。这些信息对于理解DNA通过纳米孔的易位具有重要意义，并进一步为实验的合理设计提供了知识基础。

DESCRIPTION (provided by applicant): The goal of this proposal seeks to develop a continuum-based mathematical model to gain a fundamental knowledge necessary to design a label-free, low-cost, high-speed, and high-throughput DNA sequencing method using nanopores. Nanopores are emerging as a promising candidate for the development of a third- generation sequencing device which will meet the goal of a $1,000 human genome sequencing paradigm set by the National Institute of Health. Many experimental data on DNA molecule translocation through a nanopore has been collected for the last decade, but a simple continuum-based model that describes the translocation process in statistical terms and can be directly compared with an ensemble average observed by experiments is still lacking. Limited existing analytical continuum models still cannot fully explain experimental observations. Simple physical arguments suggest that concentration polarization and the shape of the nanopore may be able to bridge the discrepancy of the tether force or translocation velocity between the experimental results and the theoretical predictions from existing simple continuum models. Thus the specific aims are to (1) Explore the role of concentration polarization using our proposed continuum-based mathematical model; (2) Examine the feasibility of using salt concentration imposed externally across the nanopore to regulate DNA translocation through numerical simulations; (3) Understand the effect of irregular shape of nanopores on DNA translocation. More accurate explicit relations between the translocation velocity and various conditions (e.g., salt concentration, nanopore dimension, surface charge, and the electric field intensity) will be determined by the proposed continuum model and ready to be directly compared with large amount of existing experimental data. Such information is important to understand the DNA translocation through a nanopore and further provides a knowledge base for rational design of experiments.