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Error analysis and parameter estimation for nanopore based molecular detection

  • Author(s): O'Donnell, Christopher Ryan
  • Advisor(s): Dunbar, William B
  • Sanfelice, Ricardo
  • et al.
Abstract

Nanopores are powerful tools for measuring and probing single molecules. A nanopore is a nanometer-sized opening in a membrane that separates two chambers filled with buffered ionic solution. By applying a voltage and measuring the ionic current through the nanopore, it is possible to detect the presence of individual DNA, RNA and proteins as they pass through the pore, and even read the sequence of individual nucleobases that make up a single strand of DNA. However, the speed with which molecules translocate and the size of the sensing region have presented challenges for using nanopores to sequence DNA. Most nanopore-based DNA sequencing research focuses on using biological nanopores paired with an enzyme to slow down the passage of DNA through the pore, but recent advances in solid-state fabrication technology have made it possible to create artificial solid-state nanopores in insulating membranes, typically made of silicon. These pores can be made in a larger range of sizes, are more durable, and are more amenable to large scale fabrication than their biological counterparts. In order to control the rate of molecular translocation through solid-state nanopores, researchers are developing a two-pore architecture, which utilizes time-varying voltage patterns to enable rereading of individual molecules to gain confidence in feature sensing. This thesis presents a numerical study that provides an error analysis of an idealized nanopore sequencing method in which ionic current measurements are used to sequence intact single-stranded DNA in the pore while an enzyme controls DNA motion. This analysis presents examples of systematic and random errors associated with this method of sequencing and demonstrates the necessity of rereading sequences at least 140 times to achieve 99.99% accuracy. Two different methods of parameter estimation are then presented that overcome the problem of contamination of the measured ionic current by capacitive elements in the system and facilitate active control with the two-pore architecture.

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