Guanidine-II aptamer conformations and ligand binding modes through the lens of molecular simulation |
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Authors: | Jakob Steuer,Oleksandra Kukharenko,Kai Riedmiller,Jö rg S Hartig,Christine Peter |
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Affiliation: | Department of Chemistry, University of Konstanz, 78457 Konstanz, Germany;Konstanz Research School Chemical Biology (KoRS-CB), University of Konstanz, 78457 Konstanz, Germany;Max Planck Institute for Polymer Research, 55128 Mainz, Germany |
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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. |
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