Entropy-driven conformational transition of flexible Z-DNA to a novel non-B helix by double-methylated guanosine

Developing chemical modifications of DNA to find drug targets is challenging. Here, we incorporated double-methylated guanosine into a DNA duplex and determined its solution structure using NMR and restrained molecular dynamics. The double-methylation of guanosine promotes aberrantly distorted Z-DNA with a widened groove space. This flexible Z-DNA exhibited slow conformational exchange (second time-scale) with a novel helical structure (denoted as tBZ-form). We find three characteristics of the Z-to-tBZ transition: 1) syn-to-syn glycosidic conformation (Z-to-non-B); 2) loss of left-handedness (that is, Z-to-non-Z); 3) entropic gain of the Z-to-tBZ transition. We anticipate that this flexible Z-DNA can be considered a novel target for drug discovery and that the Z-to-tBZ transition will provide new insights into structural diversity.