Binding free energy decomposition and multiple unbinding paths of buried ligands in a PreQ1 riboswitch.

Riboswitches are naturally occurring RNA elements that control bacterial gene expression by binding to specific small molecules. They serve as important models for RNA-small molecule recognition and have also become a novel class of targets for developing antibiotics. Here, we carried out convention...

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Autores principales:	Guodong Hu, Huan-Xiang Zhou
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/d91d631acf674b03bf4c04f4c7c37a31
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spelling	oai:doaj.org-article:d91d631acf674b03bf4c04f4c7c37a312021-12-02T19:58:11ZBinding free energy decomposition and multiple unbinding paths of buried ligands in a PreQ1 riboswitch.1553-734X1553-735810.1371/journal.pcbi.1009603https://doaj.org/article/d91d631acf674b03bf4c04f4c7c37a312021-11-01T00:00:00Zhttps://doi.org/10.1371/journal.pcbi.1009603https://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358Riboswitches are naturally occurring RNA elements that control bacterial gene expression by binding to specific small molecules. They serve as important models for RNA-small molecule recognition and have also become a novel class of targets for developing antibiotics. Here, we carried out conventional and enhanced-sampling molecular dynamics (MD) simulations, totaling 153.5 μs, to characterize the determinants of binding free energies and unbinding paths for the cognate and synthetic ligands of a PreQ1 riboswitch. Binding free energy analysis showed that two triplets of nucleotides, U6-C15-A29 and G5-G11-C16, contribute the most to the binding of the cognate ligands, by hydrogen bonding and by base stacking, respectively. Mg2+ ions are essential in stabilizing the binding pocket. For the synthetic ligands, the hydrogen-bonding contributions of the U6-C15-A29 triplet are significantly compromised, and the bound state resembles the apo state in several respects, including the disengagement of the C15-A14-A13 and A32-G33 base stacks. The bulkier synthetic ligands lead to significantly loosening of the binding pocket, including extrusion of the C15 nucleobase and a widening of the C15-C30 groove. Enhanced-sampling simulations further revealed that the cognate and synthetic ligands unbind in almost opposite directions. Our work offers new insight for designing riboswitch ligands.Guodong HuHuan-Xiang ZhouPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 17, Iss 11, p e1009603 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Guodong Hu Huan-Xiang Zhou Binding free energy decomposition and multiple unbinding paths of buried ligands in a PreQ1 riboswitch.
description	Riboswitches are naturally occurring RNA elements that control bacterial gene expression by binding to specific small molecules. They serve as important models for RNA-small molecule recognition and have also become a novel class of targets for developing antibiotics. Here, we carried out conventional and enhanced-sampling molecular dynamics (MD) simulations, totaling 153.5 μs, to characterize the determinants of binding free energies and unbinding paths for the cognate and synthetic ligands of a PreQ1 riboswitch. Binding free energy analysis showed that two triplets of nucleotides, U6-C15-A29 and G5-G11-C16, contribute the most to the binding of the cognate ligands, by hydrogen bonding and by base stacking, respectively. Mg2+ ions are essential in stabilizing the binding pocket. For the synthetic ligands, the hydrogen-bonding contributions of the U6-C15-A29 triplet are significantly compromised, and the bound state resembles the apo state in several respects, including the disengagement of the C15-A14-A13 and A32-G33 base stacks. The bulkier synthetic ligands lead to significantly loosening of the binding pocket, including extrusion of the C15 nucleobase and a widening of the C15-C30 groove. Enhanced-sampling simulations further revealed that the cognate and synthetic ligands unbind in almost opposite directions. Our work offers new insight for designing riboswitch ligands.
format	article
author	Guodong Hu Huan-Xiang Zhou
author_facet	Guodong Hu Huan-Xiang Zhou
author_sort	Guodong Hu
title	Binding free energy decomposition and multiple unbinding paths of buried ligands in a PreQ1 riboswitch.
title_short	Binding free energy decomposition and multiple unbinding paths of buried ligands in a PreQ1 riboswitch.
title_full	Binding free energy decomposition and multiple unbinding paths of buried ligands in a PreQ1 riboswitch.
title_fullStr	Binding free energy decomposition and multiple unbinding paths of buried ligands in a PreQ1 riboswitch.
title_full_unstemmed	Binding free energy decomposition and multiple unbinding paths of buried ligands in a PreQ1 riboswitch.
title_sort	binding free energy decomposition and multiple unbinding paths of buried ligands in a preq1 riboswitch.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/d91d631acf674b03bf4c04f4c7c37a31
work_keys_str_mv	AT guodonghu bindingfreeenergydecompositionandmultipleunbindingpathsofburiedligandsinapreq1riboswitch AT huanxiangzhou bindingfreeenergydecompositionandmultipleunbindingpathsofburiedligandsinapreq1riboswitch
_version_	1718375809583939584

Binding free energy decomposition and multiple unbinding paths of buried ligands in a PreQ1 riboswitch.

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