NER: Molecular Dynamics Study of the Transverse Current During the Translocation of DNA Through a Fabricated Nanopore

0103140 Cui本提案是针对NSE、NSF-0019而收到的。将探索一种有前景的快速DNA测序的新方法。分子动力学模拟将被用来确定所提出的方法的潜在可行性，该方法是通过轴向电场驱动的人工制造的纳米横截面沟道来分解水电解质介质中的单链DNA的单个碱基。电流变化的大小和持续时间将在一对横向于通道轴的偏置电极之间确定，因为在电极之间驱动完全拉长的DNA链上的单个碱基。在这一计算中要探讨的关键可行性问题是给定碱基的当前签名的重复性、一个碱基的签名与其他碱基的签名的可区分性以及签名与随机波动相比的大小。如果计算证明了这种方法的可行性，将有强烈的动机从实验和计算上进一步研究它，因为它提供了将DNA测序从基于桑格方法的现有技术每秒约0.3个碱基加快到可能数百万到数十亿个碱基每秒的可能性。这种快速测序可以在适用于个体诊断和基于基因组的治疗的时间、规模和成本内对个体基因组进行测序。当今存在的技术原则上允许用与单个基座的尺寸相当的嵌入电极制造约2 nm横截面的沟道。这类系统有望在未来几年内实现实验。在电驱动下通过天然膜中的纳米蛋白质孔进行DNA和RNA检测的实验已经引起了人们的极大兴趣，但这些系统远远达不到拟用于研究的制造通道的前景，而且还有许多其他缺点。拟议的探索性模拟的成功肯定会刺激和指导实现实验的努力，并将为优化和理解这些未来的实验提供工具。

0103140CuiThis proposal was received in response to NSE, NSF-0019. A promising new method for rapid DNA sequencing will be explored. Molecular dynamics simulations will be performed to establish the potential feasibility of a proposed method for resolving individual bases of single-strand DNA in aqueous electrolyte medium being driven through an artificially fabricated channel of nanometer cross section by an axial electric field. The magnitude and duration of electrical current variations will be determined between a pair of biased electrodes positioned transverse to the channel axis, as individual bases on the fully-elongated DNA strand are driven between the electrodes. The crucial feasibility issues to be explored in this calculation are the reproducibility of the current signature of a given base, the distinguishability of one base's signature from others', and the magnitude of the signature compared with random fluctuations. If calculations demonstrate the feasibility of this approach, there will be strong incentive to study it further both experimentally and computationally, for it offers the potential to speed up DNA sequencing from ca. 0.3 bases per second using current technology based on the Sanger method to perhaps millions to billions of bases per second. Such rapid sequencing could enable sequencing of an individual genome within time scale and cost appropriate for individual diagnostics and genome-based treatment. Techniques exist today that, in principle, allow fabrication of channels of ca. 2 nm cross section with embedded electrodes of dimensions comparable to those of a single base. Experimental realization of such systems is expected within the next few years. Already, experiments with DNA and RNA detection during electrically-driven flow through nanometer scale protein pores in natural membranes have excited great interest, but these systems fall far short of the promise of the fabricated channels proposed for study and have many other disadvantages, as well. Success in the proposed exploratory simulations is certain to stimulate and guide efforts toward experimental realization and will provide the tools for optimizing and understanding these future experiments.