Rational design of aptamer switches with programmable pH response

Ian A. P. Thompson, Liwei Zheng, Michael Eisenstein and H. Tom Soh ()
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Ian A. P. Thompson: Stanford University
Liwei Zheng: Stanford University
Michael Eisenstein: Stanford University
H. Tom Soh: Stanford University

Nature Communications, 2020, vol. 11, issue 1, 1-7

Abstract: Abstract Aptamer switches that respond sensitively to pH could enhance control over molecular devices, improving their diagnostic and therapeutic efficacy. Previous designs have inserted pH-sensitive DNA motifs into aptamer sequences. Unfortunately, their performance was limited by the motifs’ intrinsic pH-responses and could not be tuned to operate across arbitrary pH ranges. Here, we present a methodology for converting virtually any aptamer into a molecular switch with pH-selective binding properties — in acidic, neutral, or alkaline conditions. Our design inserts two orthogonal motifs that can be manipulated in parallel to tune pH-sensitivity without altering the aptamer sequence itself. From a single ATP aptamer, we engineer pH-controlled target binding under diverse conditions, achieving pH-induced selectivity in affinity of up to 1,000-fold. Importantly, we demonstrate the design of tightly regulated aptamers with strong target affinity over only a narrow pH range. Our approach offers a highly generalizable strategy for integrating pH-responsiveness into molecular devices.

Date: 2020
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DOI: 10.1038/s41467-020-16808-2

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