Work

Designing molecular RNA switches with Restricted Boltzmann machines

Year: 2025

Type: article

Abstract: Riboswitches are structured allosteric RNA molecules that change conformation upon metabolite binding, triggering a regulatory response. Here we focus on the de novo design of riboswitch-like aptamers, the core part of the riboswitch undergoing structural changes. We use Restricted Boltzmann machines (RBM) to learn generative models from homologous sequence data. We first verify, on four different riboswitch families, that RBM-generated sequences correctly capture the conservation, covariation and diversity of natural aptamers. The RBM model is then used to design new SAM-I riboswitch aptamers. To experimentally validate the properties of the structural switch in designed molecules, we resort to chemical probing (SHAPE and DMS), and develop a tailored analysis pipeline adequate for high-throughput tests of diverse sequences. We probe a total of 476 RBM-designed and 201 natural sequences. Designed molecules with high RBM scores, with 20% to 40% divergence from any natural sequence, display ≈ 30% success rate of responding to SAM with a structural switch similar to their natural counterparts. We show how the capability of the designed molecules to switch conformation is connected to fine energetic features of their structural components.

Source: Nature Communications

DOI: 10.1038/s41467-025-66265-y