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X\u2010ray crystal structures have been determined for the ligand\u2010free state for representatives of the preQ<jats:sub>1<\/jats:sub>\u2010I, <jats:italic>S<\/jats:italic>\u2010adenosylmethionine I, lysine, and glycine aptamer classes. These structures in conjunction with complimentary techniques, such as in\u2010line probing, NMR spectroscopy, F\u00f6rster resonance energy transfer, small\u2010angle scattering, and computational simulations, have demonstrated that riboswitches adopt multiple conformations in the absence of ligand. Despite a number of investigations that support ligand\u2010dependent folding, mounting evidence suggests that free\u2010state riboswitches interact with their effectors in the sub\u2010populations of largely prefolded states as embodied by the principle of conformational selection, which has been documented extensively for protein\u2010mediated ligand interactions. Fundamental riboswitch investigations of the bound and free states have advanced our understanding of RNA folding, ligand recognition, and how these factors culminate in communication between an aptamer and its expression platform. An understanding of these topics is essential to comprehend riboswitch gene regulation at the molecular level, which has already provided a basis to understand the mechanism of action of natural antimicrobials. <jats:italic>WIREs RNA<\/jats:italic> 2012, 3:369\u2013384. doi: 10.1002\/wrna.114.<\/jats:p><jats:p>This article is categorized under:\n<jats:list list-type=\"explicit-label\">\n<jats:list-item><jats:p>RNA Structure and Dynamics &gt; Influence of RNA Structure in Biological Systems<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Regulatory RNAs\/RNAi\/Riboswitches &gt; Riboswitches<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>RNA Interactions with Proteins and Other Molecules &gt; Small Molecule\u2013RNA Interactions<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p>","DOI":"10.1002\/wrna.114","type":"journal-article","created":{"date-parts":[[2011,9,28]],"date-time":"2011-09-28T15:01:58Z","timestamp":1317222118000},"page":"369-384","source":"Crossref","is-referenced-by-count":56,"title":["Riboswitch structure in the ligand\u2010free state"],"prefix":"10.1002","volume":"3","author":[{"given":"Joseph A.","family":"Liberman","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph E.","family":"Wedekind","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2011,9,28]]},"reference":[{"key":"e_1_2_6_1_2_1","unstructured":"Rfam rfam.sanger.ac.uk(A database comprising a collection of RNA families derived from multiple sequence alignments consensus secondary structures and covariance analysis)."},{"key":"e_1_2_6_1_3_1","unstructured":"Protein Data 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