Identifying small-molecules binding sites in RNA conformational ensembles with SHAMAN

Abstract

The rational targeting of RNA with small molecules is hampered by our still limited understanding of RNA structural and dynamic properties. Mostin silicotools for binding site identification rely on static structures and therefore cannot face the challenges posed by the dynamic nature of RNA molecules. Here we present SHAMAN, a computational technique to identify potential small-molecule binding sites in RNA structural ensembles. SHAMAN enables exploring the conformational landscape of RNA with atomistic molecular dynamics and at the same time identifying RNA pockets in an efficient way with the aid of probes and enhanced-sampling techniques. In our benchmark composed of large, structured riboswitches as well as small, flexible viral RNAs, SHAMAN successfully identified all the experimentally resolved pockets and ranked them among the most favorite probe hotspots. Overall, SHAMAN sets a solid foundation for future drug design efforts targeting RNA with small molecules, effectively addressing the long-standing challenges in the field.

The Study of Molecules and Processes in Solution: An Overview of Questions, Approaches and Applications

“…Lang and co-workers compiled a test set of RNA-ligand complexes to validate the ability of the DOCK suite of programmes to recreate experimentally determined binding poses; they noted that the success rate increases to 80% when docking-obtained conformations are rescored with the PBSA and GBSA implicit solvent models in combination with explicit water molecules and sodium counterions [351]. Panei and co-workers designed a computational technique to identify potential binding sites for small molecules in RNA structural ensembles and included the solvent consideration in the corresponding software [352].…”

“…Yusof and co-workers used spectroscopic analysis and MD simulations to investigate the binding characteristics of calf thymus DNA in a tetrabutylammonium-bromide-based DES [353]. DNA-templated silver clusters with up to about 30 silver atoms have proven to be bright emitters in the visible to near-infrared range, with the phenomenon controlled by the selected DNA sequence [352]. Malola and co-workers studied the DNA-stabilised silver cluster Ag 16 Cl 2 in aqueous solution at the DFT level, using an implicit solvent model, and inferred that the consideration of explicit solvent molecules at the DNA-water interface would be important for the study of transitions in the high-UV region [354].…”

The Study of Molecules and Processes in Solution: An Overview of Questions, Approaches and Applications

“…Lang and co-workers compiled a test-set of RNA-ligand complexes to validate the ability of the DOCK suite of programs to recreate experimentally determined binding poses; they noted that the success rate increases to 80% when docking-obtained conformations are rescored with the PBSA and GBSA implicit solvent models in combination with explicit water molecules and sodium counterions [345]. Panei and co-workers designed a computational technique to identify potential binding sites for small-molecule in RNA structural ensembles, and included the solvent consideration in the corresponding software [346].…”

“…Yusof and co-workers used spectroscopic analysis and MD simulations to investigate the binding characteristics of calf thymus DNA in a tetrabutylammonium bromide based DES [347]. DNA-templated silver clusters with up to about 30 silver atoms have proven to be bright emitters in the visible to near-infrared range, with the phenomenon controlled by the selected DNA sequence [346]. Malola and co-workers studied the DNA-stabilized silver cluster Ag16Cl2 in aqueous solution at the DFT level, using an implicit solvent model, and inferred that the consideration of explicit solvent molecules at the DNA−water interface would be important for the study of transitions in the high-UV region [348].…”