Locked nucleic acid building blocks as versatile tools for advanced G-quadruplex design

A hybrid-type G-quadruplex is modified with LNA (locked nucleic acid) and 2′-F-riboguanosine in various combinations at the two syn positions of its third antiparallel G-tract. LNA substitution in the central tetrad causes a complete rearrangement to either a V-loop or antiparallel structure, depending on further modifications at the 5′-neighboring site. In the two distinct structural contexts, LNA-induced stabilization is most effective compared to modifications with other G surrogates, highlighting a potential use of LNA residues for designing not only parallel but various more complex G4 structures. For instance, the conventional V-loop is a structural element strongly favored by an LNA modification at the V-loop 3′-end in contrast with an alternative V-loop, clearly distinguishable by altered conformational properties and base-backbone interactions as shown in a detailed analysis of V-loop structures.