Binding Free energy Decomposition and Multiple Unbinding Paths of Buried Ligands in a PreQ1 Riboswitch
| Autor: | Guodong Hu, Huan-Xiang Zhou |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Riboswitch
Molecular Dynamics Ligands Physical Chemistry Biochemistry Nucleobase Molecular dynamics Computational Chemistry Nucleic Acids Biochemical Simulations Ribozymes Biology (General) Free Energy Crystallography Ecology Nucleotides Hydrogen bond Chemistry Physics Condensed Matter Physics Small molecule PreQ1 riboswitch Enzymes Computational Theory and Mathematics Modeling and Simulation Physical Sciences Crystal Structure Thermodynamics Research Article QH301-705.5 Stereochemistry Stacking Cellular and Molecular Neuroscience Genetics Solid State Physics Molecule Molecular Biology Ecology Evolution Behavior and Systematics Nucleobases Binding Sites Chemical Bonding Biology and Life Sciences Computational Biology Proteins Hydrogen Bonding Riboswitches Enzymology RNA |
| Zdroj: | PLoS Computational Biology PLoS Computational Biology, Vol 17, Iss 11, p e1009603 (2021) |
| DOI: | 10.1101/2021.07.13.452201 |
| Popis: | 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. Author summary Riboswitches are bacterial RNA elements that change structures upon binding a cognate ligand. They are of great interest not only for understanding gene regulation but also as targets for designing small-molecule antibiotics and chemical tools. Understanding the molecular determinants for ligand affinity and selectivity is thus crucial for designing synthetic ligands. Here we carried out extensive molecular dynamics simulations of a PreQ1 riboswitch bound to either cognate or synthetic ligands. By comparing and contrasting these two groups of ligands, we learn how the chemical (e.g., number of hydrogen bond donors and acceptors) and physical (e.g., molecular size) features of ligands affect binding affinity and ligand exit paths. While the number of hydrogen bond donors and acceptors is a key determinant for RNA binding affinity, the ligand size affects the rigidity of the binding pocket and thereby regulates the unbinding of the ligand. These lessons provide guidance for designing riboswitch ligands. |
| Databáze: | OpenAIRE |
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