Force-Modulated Hybridization for Single-Nucleotide Nucleic Acid Length Measurement
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Solution Overview
Problem
Current methods for measuring nucleic acid length and interactions lack single-nucleotide resolution and require expensive instrumentation, making it challenging to precisely determine the exact interacting sites of nucleic acids with other biological entities.
Innovation Solution
The use of magnetically labeled oligonucleotide strands and oligonucleotide ruler strands in a force-modulated hybridization process, where mechanical force is applied to determine the length and sequence of nucleic acids by observing immobilized particles on a functionalized surface, allowing for single-nucleotide resolution without the need for expensive equipment.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If current methods for measuring nucleic acid length are used, then measurement can be performed, but single-nucleotide resolution cannot be achieved
Solution Approach 1:
The invention uses a series of oligonucleotide ruler strands of different lengths (e.g., 10-mer, 11-mer, 12-mer, etc.) to segment the measurement range into discrete single-nucleotide increments. By testing which ruler strand length produces immobilized particles, the exact length of the analyte strand is determined with single-nucleotide precision without requiring complex instrumentation.
Solution Approach 2:
The invention changes the length parameter of the oligonucleotide ruler strands systematically (10-mer, 11-mer, 12-mer, etc.) to probe the analyte strand length. This parameter variation allows precise determination of the analyte length by identifying the critical ruler strand length that transitions from producing to not producing immobilized particles.
2Measurement precision
If expensive instrumentation is used for measuring nucleic acid interactions, then measurement capability is improved, but cost and device complexity increase
Solution Approach 1:
The invention replaces complex optical or electronic measurement systems with a simple mechanical force application system. By applying mechanical force to pull on the magnetically labeled oligonucleotide strand, the system determines nucleic acid length and interactions through the presence or absence of immobilized particles, eliminating the need for expensive microscopy or spectroscopy equipment.
Solution Approach 2:
The invention uses magnetic labels that produce visually observable changes (immobilized particles visible to the naked eye or with simple microscopy) instead of requiring complex optical detection systems. The magnetic labels provide a clear visual signal that indicates whether hybridization occurred, enabling measurement without expensive instrumentation.
3Measurement precision
If mechanical force is applied to determine nucleic acid length, then single-nucleotide resolution is achieved, but measurement complexity increases
Solution Approach 1:
The invention performs preliminary hybridization between the magnetically labeled oligonucleotide strand and the analyte strand before applying mechanical force. This preliminary action creates a stable complex that can withstand the subsequent force application, allowing the force to be used purely for measurement rather than also for complex assembly.
Solution Approach 2:
The magnetically labeled oligonucleotide strand serves as an intermediary that connects the analyte strand to the mechanical force application system. This intermediary molecule allows force to be transmitted to the analyte for length determination while providing a magnetic label for easy detection of the measurement outcome.
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 method enables precise measurement of nucleic acid length and sequence with single-nucleotide resolution, visually observable without expensive apparatus, facilitating the determination of binding sites and interactions, and can be applied in various biological conditions.
Implementation Method 1
incubating a magnetically labeled oligonucleotide strand, the analyte strand, and one of a series of oligonucleotide ruler strands to form a mixture, where the magnetically labeled oligonucleotide strand is complementary in sequence to the analyte strand
Implementation Method 2
transferring the mixture to a surface functionalized to couple with the at least one label
Implementation Method 3
applying a mechanical force to the mixture; and inspecting the surface for immobilized particles
Data Source
AI summary
Embodiments of the present disclosure pertain to methods of utilizing force-modulated hybridization to determine the length of an analyte strand, to determine an unknown nucleic acid sequence, or to determine the binding of a nucleotide to an active agent. Additional embodiments of the present disclosure pertain to sample holder devices and methods of utilizing such devices. Further embodiments of the present disclosure pertain to detection devices.