Aptamers, single-stranded oligonucleotides with high binding specificity, can be identified for most molecular targets via the in vitro selection process known as SELEX (Systematic Evolution of Ligands by Exponential Enrichment). The relative efficiency and robusticity of SELEX as well as a low rate of immunogenicity make aptamers promising candidates for diagnostic and therapeutic applications. However, the mechanisms underlying aptamer-ligand recognition and subsequent folding events are not well understood. We are applying all-atom, molecular dynamics (MD) simulations to investigate these processes for application to improved aptamer design. Conventional and enhanced sampling MD simulations of the 35-nt, RNA aptamer for flavin mononucleotide (FMNapt) were preformed. Apo and ligand-bound systems were simulated to explore their respective conformational ensembles and examine RNA force field parameters. Previous NMR characterization of the FMNapt revealed a disordered internal loop in the apo state, which folded to accommodate FMN in the bound structure. We observed that while this loop is less stable in the apo state it maintains a degree of preorganization through an internal adenine, A11, which rotates to participate in FMN-like interactions. Simulations of modified FMNapt systems were performed and revealed altered binding modes, further informing on key FMNapt binding interactions. Additionally, native-contact models were employed to capture known base pairing and stacking interactions in folding simulations.

Examining ligand recognition in RNA aptamers via molecular dynamics simulations

253rd National Meeting (2017)

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