Key result
Molecular dynamics simulations show RNA-inhibitor complexes are stable in crystal but not NMR conformations.
Why the study?
Very few drugs have been designed or found to target RNA despite its many biological functions.
Standard MM-GBSA and MM-PBSA methods may be unsuitable for ranking binding energies of highly charged RNA-inhibitor complexes, whereas simple binding enthalpy calculations based on explicitly solvated potential energies provide better correlation with experimental data.
MD stability supports 2-aminobenzimidazole optimization for HCV IRES; leaves open experimental validation and clinical translation.
Despite the many biological functions of RNA, very few drugs have been designed or found to target RNA. Here we report the results of molecular dynamics (MD) simulations and binding energy analyses on hepatitis C virus internal ribosome entry site (IRES) RNA in complex with highly charged 2-aminobenzimidazole inhibitors. Initial coordinates were taken from NMR and crystallography studies that had yielded different binding modes. During MD simulations, the RNA-inhibitor complex is stable in the crystal conformation but not in the NMR conformation. Additionally, we found that existing and standard MD trajectory postprocessing free energy methods, such as the MM-GBSA and MM-PBSA approaches available in AMBER, seem unsuitable to properly rank the binding energies of complexes between highly charged molecules. A better correlation with the experimental data was found using a rather simple binding enthalpy calculation based on the explicitly solvated potential energies. In anticipation of further growth in the use of small molecules to target RNA, we include results addressing the impact of charge assignment on docking, the structural role of magnesium in the IRES-inhibitor complex, the entropic contribution to binding energy, and simulations of a plausible scaffold design for new inhibitors.
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Henriksen et al. (2014) studied Hepatitis C Virus. 2-aminobenzimidazole inhibitors was evaluated on Binding energy and stability of RNA-inhibitor complex. Molecular dynamics simulations showed the RNA-inhibitor complex is stable in crystal but not NMR conformation, and standard free energy methods were unsuitable for ranking highly charged complexes.
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