Guanidine-II aptamer conformations and ligand binding modes through the lens of molecular simulation

• Published in: Nucleic acids research 2021-08, Vol.49 (14), p.7954-7965
• Main Authors: Steuer, Jakob, Kukharenko, Oleksandra, Riedmiller, Kai, Hartig, Jörg S, Peter, Christine
• Format: Article
• Language: English
• Subjects: Computational Biology
• ISSN: 0305-1048; 1362-4962
• DOI: 10.1093/nar/gkab592

Abstract Regulation of gene expression via riboswitches is a widespread mechanism in bacteria. Here, we investigate ligand binding of a member of the guanidine sensing riboswitch family, the guanidine-II riboswitch (Gd-II). It consists of two stem–loops forming a dimer upon ligand binding. Using extensive molecular dynamics simulations we have identified conformational states corresponding to ligand-bound and unbound states in a monomeric stem–loop of Gd-II and studied the selectivity of this binding. To characterize these states and ligand-dependent conformational changes we applied a combination of dimensionality reduction, clustering, and feature selection methods. In absence of a ligand, the shape of the binding pocket alternates between the conformation observed in presence of guanidinium and a collapsed conformation, which is associated with a deformation of the dimerization interface. Furthermore, the structural features responsible for the ability to discriminate against closely related analogs of guanidine are resolved. Based on these insights, we propose a mechanism that couples ligand binding to aptamer dimerization in the Gd-II system, demonstrating the value of computational methods in the field of nucleic acids research.