Tuning the Performance of Synthetic Riboswitches using Machine Learning

Riboswitch development for clinical, technological, and synthetic biology applications constantly seeks to optimize regulatory behavior. Here, we present a machine learning approach to improve the regulation of a tetracycline (tc)-dependent riboswitch device composed of two individual tc aptamers. We developed a bioinformatics model that combines random forest analysis with a convolutional neural network to predict the switching behavior of such tandem riboswitches. We found that both biophysical parameters and the hydrogen bond pattern influence regulation. Our new design pipeline led to significant improvement of the tc riboswitch device with a dynamic range extension from 8.5 to 40-fold. We are confident that our novel method not only results in an excellent tc-dependent riboswitch device but further holds great promise and potential for the optimization of other riboswitches.