Conformational Probes for Nucleic Acid Sequencing

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Solution Overview

Problem

Current nucleic acid sequencing technologies are inefficient and costly, limiting the ability to sequence large numbers of genomes needed to understand genetic correlations with human characteristics and inform personalized medicine.

Innovation Solution

A method involving conformationally labeled polymerases or exonucleases that catalyze sequential addition or removal of nucleotides, producing distinguishable conformational signal changes for each nucleotide species, allowing for the determination of nucleotide sequences and identification of modified bases.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Productivity

If conventional nucleic acid sequencing technologies are used, then sequencing can be performed, but the process is inefficient and costly, limiting the ability to sequence large numbers of genomes

Engineering Contradiction:

Improvesequencing efficiencyVSAvoidnumber of genomes that can be sequenced

Core Design Contradiction:

ProductivityVSQuantity of substance

Solution Approach 1:

The patent changes the fundamental parameter of detection from chemical signal to conformational signal. By labeling the polymerase with a conformational probe that changes fluorescence properties upon nucleotide binding, the system enables direct observation of the enzymatic mechanism, leading to higher sequencing efficiency and lower costs.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent replaces conventional chemical sequencing methods with a biophysical approach using conformational changes detected through fluorescence microscopy. This substitution of detection mechanism enables more efficient sequencing by directly observing the polymerase conformational transitions during nucleotide incorporation.

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

2Reliability

If more genomes are sequenced to understand genetic correlations, then scientific understanding improves, but time and cost increase significantly

Engineering Contradiction:

Improvescientific understanding of genetic correlationsVSAvoidtime required for genomic sequencing

Core Design Contradiction:

ReliabilityVSLoss of time

Solution Approach 1:

By fundamentally changing the detection parameter from indirect chemical signals to direct conformational fluorescence signals, the patent enables faster and more accurate sequencing, thereby reducing the time required to sequence the tens of thousands of genomes needed for comprehensive genetic correlation studies.

Inventive Principle:

Principle #35Parameter changes

3Measurement precision

If conventional sequencing methods are used, then nucleotide sequences can be determined, but the cost remains high for large-scale studies

Engineering Contradiction:

Improvenucleotide sequence determination accuracyVSAvoidcost-effectiveness of sequencing

Core Design Contradiction:

Measurement precisionVSEase of manufacture

Solution Approach 1:

The patent replaces expensive conventional sequencing chemistry with a simpler biophysical detection system based on conformational fluorescence changes. This substitution maintains sequencing accuracy while significantly reducing the cost per base, making large-scale genomic studies economically feasible.

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

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 efficient and cost-effective sequencing of nucleic acids, allowing for the determination of nucleotide sequences and identification of modified bases, which can inform personalized medicine and reduce the costs of genetic correlation studies.

Implementation Method 1

the sequential addition of each different nucleotide species produces a conformational signal change from the conformationally labeled polymerase and wherein the rate or time duration for the conformational signal change is distinguishable for each different nucleotide species

Methodology Applied

Scientific EffectConformational change:

Implementation Method 2

the sequential removal of each different nucleotide species produces a conformational signal change from the conformationally labeled exonuclease and wherein the rate or time duration for the conformational signal change is distinguishable for each different nucleotide species that is removed

Methodology Applied

Scientific EffectConformational change:

Data Source

PatentUS12297498B2Conformational probes and methods for sequencing nucleic acids

Publication Date: 2025.05.13 ILLUMINA INC

AI summary

This disclosure provides a method of determining a sequence of nucleotides for a nucleic acid template. The method can include the steps of contacting the nucleic acid template with a conformationally labeled polymerase and at least four different nucleotide species under conditions wherein the conformationally labeled polymerase catalyzes sequential addition of the nucleotide species to form a nucleic acid complement of the nucleic acid template, wherein the sequential addition of each different nucleotide species produces a conformational signal change from the conformationally labeled polymerase and wherein the rate or time duration for the conformational signal change is distinguishable for each different nucleotide species; detecting a series of changes in the signal from the conformationally labeled polymerase under the conditions; and determining the rates or time durations for the changes in the signal, thereby determining the sequence of nucleotides for the nucleic acid template.