Tunnel Gap Device for Single Base DNA Sequencing
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Solution Overview
Problem
Current DNA sequencing methods, such as nanopore sequencing, face challenges in achieving single base resolution due to thermal motion and the need for multiple readers to differentiate between DNA bases, which complicates the process and reduces selectivity.
Innovation Solution
The development of a device with electrodes functionalized with reagents capable of forming transient bonds with DNA units, generating detectable signals as polymers pass through a tunnel gap, optimizing the gap width for improved selectivity and allowing for the analysis of polymers like DNA, RNA, and peptides.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If nanopore sequencing uses ion current readout, then DNA molecules can be forced through a tiny aperture using electrophoresis, but single base resolution cannot be attained because all bases in the nanopore channel contribute to the current blockade
Solution Approach 1:
The invention extracts the problematic contribution of all bases in the nanopore channel to the current blockade by transitioning from a bulk nanopore measurement to a localized tunneling gap measurement. The tunneling gap is positioned to contact only a specific region of the DNA molecule, effectively extracting the signal from individual bases rather than integrating signals from all bases in the channel.
Solution Approach 2:
The invention introduces an intermediary tunneling gap mechanism between the nanopore and the readout electrodes. This tunneling gap acts as a mediator that localizes the measurement to specific base positions, converting the non-specific ion current blockade into a localized electron tunneling signal that can resolve individual bases.
2Ease of operation
If thermal motion of molecules in the gap is present, then molecules can move naturally, but the distribution of tunnel currents broadens and selectivity is reduced
Solution Approach 1:
The invention embraces the dynamic nature of thermal motion rather than attempting to eliminate it. The system is designed to accommodate molecular movement through the tunneling gap, with the gap dimensions and measurement timing optimized to capture meaningful signals despite the dynamic environment. The transient bond formation and detection occur within the timescale of molecular fluctuations.
3Measurement precision
If chemical bonds are used to tether molecules to readout electrodes, then the range of orientations of molecules in a tunnel gap is greatly reduced, but strong bonds cannot slide from one nucleotide to the next rapidly
Solution Approach 1:
The invention changes the bonding parameter from strong covalent bonds to weaker non-covalent interactions (such as hydrogen bonds, van der Waals forces, or pi-stacking). These weaker bonds provide sufficient orientation control to reduce the range of molecular orientations in the tunnel gap, while simultaneously allowing rapid sliding and detachment as the DNA molecule moves through the gap at sequencing speeds.
4Measurement precision
If multiple readers are used to differentiate between DNA bases, then base identification can be achieved, but the process becomes complicated and selectivity is reduced
Solution Approach 1:
The invention creates a universal tunneling gap reader that can identify all four DNA bases (A, T, C, G) using a single measurement mechanism. Instead of requiring four separate readers or reagent systems, the localized electron tunneling signal provides base-specific information through a unified detection approach, simplifying the device architecture while maintaining comprehensive base identification capability.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
This approach enables the precise analysis of polymers by generating distinct signals for each nucleotide, improving read accuracy and reducing the need for multiple readers, thus enhancing the efficiency of DNA sequencing.
Implementation Method 1
electron tunneling across a DNA molecule might be localized enough to sense and identify single nucleotides
Implementation Method 2
hydrogen bonds can be used to provide chemical contrast in scanning tunneling microscope images suggesting that these weaker bonds can serve as sliding contacts to single molecules
Implementation Method 3
nanopore sequencing is an enzyme-free technique in which DNA molecules are forced through a tiny aperture using electrophoresis
Data Source
AI summary
The invention includes compositions, devices, and methods for analyzing a polymer and/or polymer unit. The polymer may be a homo or hetero-polymer such as DNA, RNA, a polysaccharide, or a peptide. The device includes electrodes that form a tunnel gap through which the polymer can pass. The electrodes are functionalized with a reagent attached thereto, and the reagent is capable of forming a transient bond to a polymer unit. When the transient bond forms between the reagent and the unit, a detectable signal is generated and used to analyze the polymer.