This 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.
