Nanopore-Anchored Reporter Tethers for Sensitive Event Detection
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Solution Overview
Problem
Existing methods for detecting molecular events, such as nucleotide incorporation by DNA polymerase, are not sufficiently robust, reproducible, or sensitive for practical applications like genome sequencing, requiring improved compositions, systems, and methods.
Innovation Solution
A nanopore-based system with a tether anchored or adjacent to the nanopore, featuring a head region anchored to the nanopore and an elongated body with a reporter region that moves within the aperture in response to molecular events, allowing for detection through electrical or optical signals.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If conventional detection methods are used for molecular events, then the detection can be performed with simple setups, but the sensitivity and reproducibility are insufficient for practical applications like genome sequencing
Solution Approach 1:
The system divides the detection function into separate components: a nanopore for molecular translocation, a tether with reporter region for signal generation, and reference electrodes for signal detection. This segmentation allows each component to be optimized independently while achieving high overall sensitivity and reproducibility for genome sequencing applications
Solution Approach 2:
A tether molecule with a reporter region acts as an intermediary between the nanopore and the detection system. The tether anchors to the nanopore and moves in response to molecular events, converting molecular motion into detectable electrical signals that enhance measurement precision
2Productivity
If conventional detection methods are used, then the system setup is simple, but the throughput and accuracy are not sufficient for demanding applications
Solution Approach 1:
The system changes key parameters including using a solid-state nanopore with controlled aperture size, employing a tether with specific electrical properties, and applying controlled voltage gradients. These parameter changes enable high-throughput detection while maintaining accuracy for genome sequencing through optimized signal-to-noise ratios and controlled molecular translocation rates
3Measurement precision
If a tether with reporter region is used to detect molecular events, then the detection sensitivity is enhanced, but the device structure becomes more complex
Solution Approach 1:
The tether structure serves multiple functions simultaneously: it anchors to the nanopore, responds to molecular events through conformational changes, generates electrical signals via the reporter region, and can be functionalized for specific target recognition. This multi-functionality enhances detection sensitivity while minimizing the need for additional separate components
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
Enhances the sensitivity and reproducibility of molecular event detection, enabling high-throughput and accurate identification of nucleotides, suitable for genome sequencing and other demanding applications.
Implementation Method 1
allowing for detection through electrical or optical signals
Implementation Method 2
allowing for detection through electrical or optical signals
Data Source
AI summary
Compositions, systems, and methods for detecting events are provided. A composition can include a nanopore including a first side, a second side, and an aperture extending through the first and second sides; and a permanent tether including head and tail regions and an elongated body disposed there between. The head region can be anchored to or adjacent to the first or second side of the nanopore. The elongated body including a reporter region can be movable within the aperture responsive to a first event occurring adjacent to the first side of the nanopore. For example, the reporter region is translationally movable toward the first side responsive to the first event, then toward the second side, then toward the first side responsive to a second event. The first event can include adding a first nucleotide to a polynucleotide. The second event can include adding a second nucleotide to the polynucleotide.