Nanoswitch Caliper Trains for High-Resolution Biomolecular Distance Mapping
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Solution Overview
Problem
Current methods for measuring intramolecular distances in biomolecules, such as proteins, are low-throughput and lack the resolution needed for high-resolution structural analysis, particularly at the single-cell level, and existing computational algorithms have limited success in determining protein structures.
Innovation Solution
The use of nucleic acid-based nanodevices, specifically Nanoswitch Caliper Trains (NCTs), which measure distances between pairs of ssDNA handles on biomolecules with high resolution and throughput, utilizing a covalently connected chain of single-stranded branched 'T-junction' oligonucleotides to track reporter moieties for distance measurements.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If conventional methods (mass spectrometry, cryo-electron tomography) are used for structural analysis, then structural information can be obtained, but the throughput is low and resolution is insufficient for single-cell analysis
Solution Approach 1:
The patent divides the structural analysis process into multiple independent measurement channels, each using a separate nucleic acid nanodevice to measure distances between specific biomolecule pairs. This segmentation allows parallel processing of multiple samples simultaneously, dramatically increasing throughput while maintaining atomic-level resolution through optical detection methods.
Solution Approach 2:
The patent introduces nucleic acid nanodevices as intermediary molecules that bridge the biomolecules of interest and the detection system. These nanodevices consist of programmable nucleic acid structures that can be designed to bind specifically to target biomolecules, enabling high-resolution distance measurements through optical detection while allowing high-throughput analysis of multiple samples.
2Productivity
If computational algorithms are used for de novo protein structure prediction, then structural models can be generated, but the success rate is limited and cannot replace experimental structures
Solution Approach 1:
The patent implements an experimental feedback mechanism where actual distance measurements obtained from nucleic acid nanodevices are used to validate and refine computational protein structure predictions. This feedback loop combines the speed of computational methods with the accuracy of experimental data, significantly improving both the success rate and reliability of de novo structure determination.
Solution Approach 2:
The patent creates a composite approach by combining computational algorithms with experimental nucleic acid nanodevice measurements. This hybrid method integrates the advantages of both computational speed and experimental accuracy, producing more reliable protein structure determinations than either method alone.
3Measurement precision
If high-resolution structural analysis is performed on individual biomolecules, then atomic-level details can be obtained, but the throughput remains low compared to bulk methods
Solution Approach 1:
The patent performs preliminary actions by pre-designing and synthesizing nucleic acid nanodevices with specific binding affinities and spacing configurations before the actual measurements. This preparation allows the measurement process itself to be rapid and direct, achieving atomic-level resolution without time-consuming iterative adjustments, thereby reducing analysis time while maintaining high precision.
Solution Approach 2:
The patent replaces complex mechanical manipulation systems with optical detection methods. Instead of using mechanical means to position and measure individual biomolecules, the invention uses nucleic acid nanodevices coupled with optical detection, which dramatically reduces measurement time while maintaining atomic-level resolution.
Data Source
AI summary
Provided herein are compositions and methods for determining the structure of individual targets by determining long-range distances within such targets.