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Protein WISDOM: A Workbench for In silico De novo Design of BioMolecules
Published on: July 25, 2013
Array-based evolution of DNA aptamers allows modelling of an explicit sequence-fitness landscape
Christopher G Knight1, Mark Platt, William Rowe
1Manchester Interdisciplinary Biocentre, The University of Manchester, Manchester, UK. chris.knight@manchester.ac.uk
Nucleic Acids Research
|November 26, 2008
Summary
Researchers mapped aptamer sequence fitness for biological function using a novel in silico evolution method. This approach enables rapid design of high-affinity aptamers, advancing nucleic acid therapeutics and diagnostics.
Area of Science:
- Biochemistry and Molecular Biology
- Bioinformatics and Computational Biology
Background:
- Understanding the relationship between macromolecular polymer sequences and their biological functions is a significant challenge.
- Aptamers, selected nucleic acids that bind specific targets, exemplify this challenge in molecular recognition.
Purpose of the Study:
- To characterize the sequence-fitness landscape for aptamers binding allophycocyanin (APC) protein.
- To develop a predictive machine learning model for aptamer binding properties.
Main Methods:
- Utilized a novel Closed Loop Aptameric Directed Evolution (CLADE) approach, performing selection and mutation in silico.
- Conducted in vitro fitness assays for 44,131 aptamers using DNA microarrays.
- Developed and validated a machine learning model linking sequence features to binding function using 5500 independent test sequences.
Main Results:
- Achieved a high observed versus predicted correlation of 0.87 in the machine learning model.
- Revealed a complex sequence-fitness mapping for aptamer binding.
- Demonstrated the rapid design of novel aptamers with desired binding properties.
Conclusions:
- The CLADE approach provides a powerful tool for mapping aptamer sequence-fitness landscapes.
- The predictive model enables efficient design of high-affinity aptamers.
- Incorporating prior knowledge into CLADE further optimizes aptamer design for tight binding.
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