Mechanism of Ligand Binding to Theophylline RNA Aptamer

• DOI: 10.1021/acs.jcim.3c01454
• Publication Date: 2024-01-16T11:50:29Z
• Authors: Sana Akhter; Zhichao Tang; Jinan Wang; Mercy Haboro; Erik D Holmstrom; Jingxin Wang; Yinglong Miao
• Keywords: Aptamer; Receptor–ligand kinetics; Riboswitch; Docking (animal)

Studying RNA-ligand interactions and quantifying their binding thermodynamics kinetics are of particular relevance in the field drug discovery. Here, we combined biochemical assays accelerated molecular simulations to investigate ligand dissociation RNA using theophylline-binding as a model system. All-atom Ligand Gaussian Molecular Dynamics method (LiGaMD) have captured repetitive theophylline caffeine RNA. Theophylline's free energy kinetic rate constants align with our experimental data, while caffeine's affinity is over 10,000 times weaker, its could not be determined. LiGaMD allowed us identify distinct low-energy conformations multiple pathways Simulations revealed "conformational selection" mechanism for flexible aptamer, which provides important mechanistic insights into model. Our findings suggest that compound docking structural ensemble representative would necessary structure-based design