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...
| Main Authors: | , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2021-11-01
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| Series: | PLoS Computational Biology |
| Online Access: | https://doi.org/10.1371/journal.pcbi.1009603 |
| _version_ | 1798025730493251584 |
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| author | Guodong Hu Huan-Xiang Zhou |
| author_facet | Guodong Hu Huan-Xiang Zhou |
| author_sort | Guodong Hu |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-11T18:23:42Z |
| format | Article |
| id | doaj.art-d91d631acf674b03bf4c04f4c7c37a31 |
| institution | Directory Open Access Journal |
| issn | 1553-734X 1553-7358 |
| language | English |
| last_indexed | 2024-04-11T18:23:42Z |
| publishDate | 2021-11-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Computational Biology |
| spelling | doaj.art-d91d631acf674b03bf4c04f4c7c37a312022-12-22T04:09:42ZengPublic Library of Science (PLoS)PLoS Computational Biology1553-734X1553-73582021-11-011711e100960310.1371/journal.pcbi.1009603Binding free energy decomposition and multiple unbinding paths of buried ligands in a PreQ1 riboswitch.Guodong HuHuan-Xiang ZhouRiboswitches 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.https://doi.org/10.1371/journal.pcbi.1009603 |
| spellingShingle | Guodong Hu Huan-Xiang Zhou Binding free energy decomposition and multiple unbinding paths of buried ligands in a PreQ1 riboswitch. PLoS Computational Biology |
| title | 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_short | 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 |
| url | https://doi.org/10.1371/journal.pcbi.1009603 |
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