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Nucleic acids not only form the basis of heredity, but are increasingly a source of novel nano-structures, -devices and drugs. This has spurred the development of chemically modified alternatives (xeno nucleic acids (XNAs)) comprising chemical configurations not found in nature to extend their chemical and functional scope. XNAs can be evolved into ligands (XNA aptamers) that bind their targets with high affinity and specificity. However, detailed investigations into structural and functional aspects of XNA aptamers have been limited. Here we describe a detailed structure-function analysis of LYS-S8-19, a 1',5'-anhydrohexitol nucleic acid (HNA) aptamer to hen egg-white lysozyme (HEL). Mapping of the aptamer interaction interface with its cognate HEL target antigen revealed interaction epitopes, affinities, kinetics and hot-spots of binding energy similar to protein ligands such as anti-HEL-nanobodies. Truncation analysis and molecular dynamics (MD) simulations suggest that the HNA aptamer core motif folds into a novel and not previously observed HNA tertiary structure, comprising non-canonical hT-hA-hT/hT-hT-hT triplet and hG4-quadruplex structures, consistent with its recognition by two different G4-specific antibodies. ispartof: Nucleic Acids Res pages:gkad592- ispartof: location:England status: Published online

Aptamers are folded oligonucleotides that bind to a specific target with a high affinity and selectivity. Originally they were composed of natural nucleic acids (RNA or DNA) that are identified in a large library through a process termed Systematic Evolution of Ligands by EXponential enrichment (SELEX). Since natural nucleic acids have short half-life in biological conditions, research shifted to aptamers composed of artificial (xeno) nucleic acids (XNA) with high resistance to chemical en enzymatic degradation. Ignorance on structure and folding of XNA-aptamers currently forms a major roadblock in their way to success. To fill this knowledge gap, computational and experimental methods will be applied in this project to unravel the conformational space that can be occupied by specific XNA species and determine the 2D and 3D structure of selected XNA-aptamers. The project will start to focus on hexitol nucleic acids (HNA) which will be studied in silico using the Assisted Model Building with Energy Refinement (AMBER) package and experimentally through Nuclear Magnetic Resonance (NMR) spectroscopy. status: published