Nucleic Acid Sensor Conductivity Switch for Single Molecule Detection
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Solution Overview
Problem
Existing biological and chemical research protocols for controlled reactions and nucleic acid sequencing lack efficient methods for single molecule detection, particularly in identifying nucleotide bases during sequencing processes.
Innovation Solution
A sensor comprising two electrodes with a modified, partially double-stranded nucleic acid polymer bridging them, featuring a gap with exposed nucleotide bases and a polymerase, which changes conductivity when a nucleotide-specific switch strand associates with these bases, enabling precise detection of nucleotide incorporation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If a target sequence forms a conductive bridge between two leads, then detection capability is improved, but the system requires complex labeling or modification of the target sequence
Solution Approach 1:
The invention extracts the labeling function from the target sequence itself and places it on the probe. The probe is modified to include conductive elements and signaling moieties directly, while the target sequence remains unmodified. This allows the target to form a conductive bridge naturally through hybridization, eliminating the need for complex target labeling procedures.
Solution Approach 2:
The probe acts as an intermediary between the target sequence and the detection system. The probe contains both the binding element (complementary to target) and the signaling element (conductive bridge with signaling moiety), mediating the interaction between the simple target sequence and the complex detection apparatus.
2Measurement precision
If conventional sensor methods are used for nucleic acid detection, then detection can be performed, but sensitivity for single molecule detection is insufficient
Solution Approach 1:
The invention uses changes in electrical conductivity (analogous to color changes in optical detection) to signal nucleotide incorporation. When a nucleotide is incorporated, it causes a conformational change or charge transfer that alters the conductivity of the probe, providing a detectable signal for single molecule events.
Solution Approach 2:
The invention replaces conventional optical or mechanical detection methods with electrical conductivity measurement. This substitution enables single molecule detection sensitivity because electrical measurements can detect very small changes in charge or conductivity that occur when a single nucleotide is incorporated.
3Productivity
If existing sequencing methods are used, then polynucleotide analysis can be performed, but efficient single molecule detection methods are lacking
Solution Approach 1:
The probe performs multiple functions autonomously: it binds to the target sequence, provides the conductive bridge, and generates the detection signal. The probe itself serves as both the capture element and the signaling element, eliminating the need for separate labeling steps and enabling direct single molecule detection during sequencing.
Solution Approach 2:
The probe is designed as a multi-functional element that combines target binding, conductivity provision, and signal generation. This universal probe design can be applied to various sequencing applications and target sequences, providing both high productivity and single molecule detection 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 allows for sensitive and accurate single molecule detection in nucleic acid sequencing by significantly altering the conductivity of the molecular nanowire, facilitating the identification of nucleotide bases during the sequencing process.
Implementation Method 1
the switch strand is selected to change the conductivity of the modified, partially double stranded nucleic acid polymer bridging the two electrodes
Implementation Method 2
a strand of nucleotides including bases complementary to the at least some of the plurality of nucleotide bases exposed at the gap
Data Source
Figure 1A~2
Figure 3A~3D
Figure 4
AI summary
A sensor includes two electrodes and a modified, partially double stranded nucleic acid polymer bridging the two electrodes. The modified, partially double stranded nucleic acid polymer includes two polynucleotide chains partially bonded together, a gap in a first of the polynucleotide chains wherein nucleotide bases are missing, and a plurality of nucleotide bases of a second of the polynucleotide chains exposed at the gap. The sensor further comprises a polymerase attached to the modified, partially double stranded nucleic acid polymer or the sensor further comprises a substrate supporting the two electrodes; and a polymerase attached to the substrate. Furthermore, a kit to assemble the sensor, a sensing system incorporating such a sensor and a method.