Macromolecule Cleavage Modeling for Modified Oligonucleotide MS/MS
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Solution Overview
Problem
Current mass spectrometry techniques face challenges in accurately determining the expected cleavage products of oligonucleotides and peptides, particularly when modifications occur at the base, sugar, or phosphate groups, which complicates the identification of MS/MS fragments and requires detailed information about modification positions and entities.
Innovation Solution
A computer-implemented method and system that represent macromolecules as sequences of residues with distinct structural units, including a base, 5′ linker, 3′ linker, and phosphate moiety, allowing for the determination of expected cleavage products by simulating bond cleavages and comparing them with experimentally observed products to confirm molecular structure correspondence.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If traditional mass spectrometry techniques are used to determine cleavage products, then the analysis can be performed with standard methods, but the accuracy of determining MS/MS fragments deteriorates when modifications occur at base, sugar, or phosphate groups
Solution Approach 1:
The patent segments the oligonucleotide molecule into distinct structural units (base, sugar, phosphate groups, and linker regions). Each unit is independently defined with its own chemical structure and bond characteristics. This segmentation allows the system to systematically analyze potential cleavage sites at each structural unit boundary, improving accuracy for modified oligonucleotides by treating modifications as specific changes to defined structural units rather than unknown variables.
Solution Approach 2:
The system changes the parameter representation from traditional sequence notation to a detailed structural model that includes specific chemical bonds, atomic compositions, and linkage types for each structural unit. By defining parameters such as bond cleavage energies, structural unit masses, and chemical connectivity, the system can accurately predict MS/MS fragmentation patterns for modified oligonucleotides while maintaining adaptability through parameter customization.
2Measurement precision
If detailed structural information about modification positions and entities is required, then the accuracy of fragment identification improves, but the complexity of the analysis process increases
Solution Approach 1:
The patent applies preliminary action by pre-defining the structural units and their possible modifications before the actual MS/MS analysis. The system establishes a library of structural units with predetermined chemical properties, bond types, and fragmentation behaviors. When analyzing an oligonucleotide, the system simply maps the sequence to these pre-defined units rather than performing complex structural analysis from scratch, thereby maintaining high accuracy while reducing computational complexity.
Solution Approach 2:
The system uses copying by creating simplified digital representations (models) of the actual oligonucleotide structure based on the sequence information. Instead of directly analyzing the complex molecular structure, the system works with copied structural data that includes essential fragmentation information. This copying approach allows accurate fragment identification without requiring direct manipulation of the complex molecular model throughout the analysis process.
3Reliability
If all significant cleavage products are accounted for, then the reliability of molecular structure confirmation improves, but the computational resources and time required increase
Solution Approach 1:
The patent applies local quality by focusing computational resources on specific high-probability cleavage sites rather than uniformly analyzing all possible bonds. The system identifies structurally significant regions (such as phosphate-sugar linkages and base-sugar connections) as primary cleavage candidates based on their chemical properties and typical MS/MS fragmentation patterns. This localized approach maintains high reliability for structure confirmation while improving productivity by avoiding exhaustive analysis of low-probability cleavage pathways.
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 significantly improves the accuracy of determining MS/MS fragments and confirms the sequence of synthetic oligonucleotides by accounting for all significant cleavage products, enhancing the reliability of molecular structure confirmation.
Implementation Method 1
The energy applied to the macromolecule can be generated via a variety of different sources and mechanisms. By way of example, the energy can be generated via a chemical reaction, particle impact, or via a radiation source (e.g., an ultraviolet radiation source), among others.
Data Source
AI summary
In one aspect, a computer implemented method for determining expected cleavage products of a macromolecule includes defining at least one residue of the macromolecule as having a core and at least one linker, where said at least one linker is defined as a sequence of two or more structural units that are coupled to one another via one or more chemical bonds. A digital data processor can be utilized to determine one or more expected bond cleavages, if any, between the structural units of said at least one linker and between adjacent residues when the macromolecule undergoes cleavage, e.g., in response to application of energy thereto, so as to predict expected cleavage products of the macromolecule.