Synthetic Macrocyclic Nanopores for High-Resolution DNA Sequencing
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Solution Overview
Problem
Current nanopore technologies, particularly those using protein nanopores, suffer from low resolution and sensitivity due to their thick sensing length, which limits their ability to achieve single-base resolution in DNA sequencing and protein sequencing.
Innovation Solution
The development of synthetic macrocyclic molecular nanopores with tunable pore size and thickness, allowing for atomic-level precision and stability through chemical modifications, enabling higher spatial resolution and efficient insertion into phospholipid bilayer membranes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If conventional protein nanopores are used for DNA sequencing, then transmembrane nanopore functionality is achieved, but spatial resolution is limited due to effective thickness greater than 2 nm
Solution Approach 1:
The patent changes the fundamental parameter of nanopore thickness by transitioning from protein-based nanopores (thickness > 2 nm) to synthetic macrocyclic nanopores (thickness < 1 nm). This parameter change enables single-base resolution in DNA sequencing by reducing the sensing length to sub-nanometer scale, directly resolving the contradiction between achieving transmembrane functionality and maintaining thin profile for high spatial resolution.
Solution Approach 2:
The patent employs synthetic macrocyclic compounds as disposable, chemically-tunable nanopore structures that can be precisely controlled at atomic levels. These synthetic structures replace expensive, complex protein structures with simpler, chemically-synthesized macrocycles that offer comparable or superior performance while enabling precise thickness control below 1 nm for high-resolution sequencing.
2Ease of operation
If protein nanopores with β-barrel structures are used, then ease of insertion into lipid bilayer membranes is improved, but resolution and sensitivity are reduced due to larger pore size
Solution Approach 1:
The patent applies local quality by designing macrocyclic structures with specific functional groups positioned at precise locations to interact with DNA bases. The macrocycle structure provides localized sensing zones within the pore that enhance detection sensitivity, while the overall molecular structure maintains compatibility with lipid bilayer insertion through appropriate hydrophobic/hydrophilic distribution.
Solution Approach 2:
The patent uses composite molecular structures combining macrocyclic frameworks with attached recognition elements (such as porphyrins, crown ethers, or other functional groups). These composite structures integrate the membrane-insertion capability of hydrophobic regions with the high-sensitivity detection capability of functional recognition groups, resolving the contradiction between ease of insertion and detection sensitivity.
3Adaptability or versatility
If larger pore sizes are used for transmembrane nanopores, then versatility in accommodating different biomolecules is improved, but spatial resolution for single-base sequencing is compromised
Solution Approach 1:
The patent segments the nanopore function into distinct regions: the macrocyclic core provides the thin sensing zone for high resolution, while peripheral functional groups and side chains provide versatility for accommodating different biomolecules. This segmentation allows the nanopore to maintain sub-nanometer thickness for single-base resolution while offering adaptable recognition sites for various DNA, RNA, or protein sequences.
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
The synthetic macrocyclic nanopores provide enhanced spatial resolution for DNA and protein sequencing, with high reproducibility and tunability, and demonstrate high potassium ion selectivity, facilitating efficient biomolecule detection and sequencing.
Implementation Method 1
the nanopore structure is a transmembrane structure with nano-sized channels formed by the insertion of the synthetic macrocyclic compound into the phospholipid bilayer membrane
Implementation Method 2
nanopores formed by macrocyclic compounds with diameters of 1 Å-15 Å can be used for selective ion transport
Data Source
AI summary
The present invention belongs to the field of bioanalysis and detection, specifically, a synthetic macrocyclic molecular nanopore structure and preparation method and application. The invention discloses an artificially synthesized macrocyclic compound to form a stable single-molecule nanopore structure on phospholipid bilayer; the nanopore structure is a transmembrane nanopore structure with nano-sized channels formed by the artificially synthesized macrocyclic compound inserted into the phospholipid bilayer membrane in electrolyte solution; the artificially synthesized macrocyclic compound solves the transmembrane nanopore cavity size and pore thickness by using the bottom up synthesis, which yields thinner pore thickness and higher freedom control of the cavity pore size compared with the traditional biological nanopores constructed by proteins.