Controlling uncertainty in aptamer selection
Name
Spill-2016-Controlling uncertainty in aptamer.pdf
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1.12 MB
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Author(s)
Spill, Fabian
Weinstein, Zohar B.
Irani Shemirani, Atena
Ho, Nga
Desai, Darash
Zaman, Muhammad H.
Date Issued
October 2016
Journal
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences (U.S.)
Citation
Spill, Fabian; Weinstein, Zohar B.; Irani Shemirani, Atena; Ho, Nga; Desai, Darash and Zaman, Muhammad H. “Controlling Uncertainty in Aptamer Selection.” Proceedings of the National Academy of Sciences 113, no. 43 (October 2016): 12076–12081. © National Academy of Sciences
Version
Final published version
Abstract
The search for high-affinity aptamers for targets such as proteins, small molecules, or cancer cells remains a formidable endeavor. Systematic Evolution of Ligands by EXponential Enrichment (SELEX) offers an iterative process to discover these aptamers through evolutionary selection of high-affinity candidates from a highly diverse random pool. This randomness dictates an unknown population distribution of fitness parameters, encoded by the binding affinities, toward SELEX targets. Adding to this uncertainty, repeating SELEX under identical conditions may lead to variable outcomes. These uncertainties pose a challenge when tuning selection pressures to isolate high-affinity ligands. Here, we present a stochastic hybrid model that describes the evolutionary selection of aptamers to explore the impact of these unknowns. To our surprise, we find that even single copies of high-affinity ligands in a pool of billions can strongly influence population dynamics, yet their survival is highly dependent on chance. We perform Monte Carlo simulations to explore the impact of environmental parameters, such as the target concentration, on selection efficiency in SELEX and identify strategies to control these uncertainties to ultimately improve the outcome and speed of this time- and resource-intensive process.
MIT Department
Massachusetts Institute of Technology. Department of Mechanical Engineering
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Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
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DOI of Published Version
https://doi.org/10.1073/pnas.1605086113
