Excited States of apo-Guanidine-III Riboswitch Contribute to Guanidinium Binding through Both Conformational and Induced-Fit Mechanisms

Singh, K and Reddy, G (2024) Excited States of apo-Guanidine-III Riboswitch Contribute to Guanidinium Binding through Both Conformational and Induced-Fit Mechanisms. In: Journal of Chemical Theory and Computation, 20 (1). pp. 421-435.

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Abstract

Riboswitches are mRNA segments that regulate gene expression through conformational changes driven by their cognate ligand binding. The ykkC motif forms a riboswitch class that selectively senses a guanidinium ion (Gdm+) and regulates the downstream expression of proteins which aid in the efflux of excess Gdm+ from the cells. The aptamer domain (AD) of the guanidine-III riboswitch forms an H-type pseudoknot with a triple helical domain that binds a Gdm+. We studied the binding of Gdm+ to the AD of the guanidine (ykkC)-III riboswitch using computer simulations to probe the specificity of the riboswitch to Gdm+ binding. We show that Gdm+ binding is a fast process occurring on the nanosecond time scale, with minimal conformational changes to the AD. Using machine learning and Markov-state models, we identified the excited conformational states of the AD, which have a high Gdm+ binding propensity, making the Gdm+ binding landscape complex exhibiting both conformational selection and induced-fit mechanisms. The proposed apo-AD excited states and their role in the ligand-sensing mechanism are amenable to experimental verification. Further, targeting these excited-state conformations in discovering new antibiotics can be explored. © 2023 American Chemical Society.

Item Type:	Journal Article
Publication:	Journal of Chemical Theory and Computation
Publisher:	American Chemical Society
Additional Information:	The copyright for this article belongs to American Chemical Society.
Keywords:	guanidine; guanidine derivative; ligand, chemistry; conformation; metabolism; riboswitch, Guanidine; Guanidines; Ligands; Nucleic Acid Conformation; Riboswitch
Department/Centre:	Division of Chemical Sciences > Solid State & Structural Chemistry Unit
Date Deposited:	01 Mar 2024 08:54
Last Modified:	01 Mar 2024 08:54
URI:	https://eprints.iisc.ac.in/id/eprint/83936

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