Rational Design of pH-Switches Based on Mismatch-Guided Hybridization of I-Motifs and G-Quadruplexes

pH-responsive DNA nanodevices and materials are attracting wide attention owing to their promising applications in medicine and nanotechnology. However, the sustainable and systematic development of molecular pH-switches based on mismatch-guided hybridization of G-quadruplexes and i-motifs lacks a rational framework for their design and analytical analysis. In this study, we formulate and rigorously analyze the principles underlying the operation of such molecular nanomachines. Using the AS1411 aptamer to nucleolin as a model G-quadruplex, we designed 19 pH-switches having a transition pH from 5.2 to 7.4 to validate our framework. Ultimately, we derived empirically grounded guidelines for the engineering of the pH-switches and thermodynamic approaches to predict their properties analytically.