The mechanics of minor groove width variation in DNA, and its implicationsfor the accommodation of ligands

In duplex DNA, groove width and depth are salient structural features that may influence the binding of drugs and proteins. These features are affecte d by movement of the bases, which for example may enforce groove compressio n or expansion through a rolling action of the adjacent base-pairs. Moreove r, the sugar-phosphate backbone can also undergo limited movement, independ ently of the bases, which will affect the groove shape. We have examined ho w the movement of the sugar-phosphate backbone may affect the minor groove width for a fixed base geometry. Ln agreement with earlier studies, the sug ar-phosphate backbone is found to have a certain degree of conformational f lexibility in A and B-like helices, and we note a comparable freedom even i n the highly curved TATA element of the TATA-binding protein/DNA complex. P hosphate mobility is highly anisotropic in all cases with favoured directio ns that can significantly change the groove width, independent of any chang es in base geometry. We describe how the movement of the sugar phosphate ba ckbone may affect the accommodation of drugs and proteins in the minor groo ve, and we present a co-ordinate scheme which emphasises the groove adjustm ents associated with ligand binding. The observations have implications for the related problem of how cognate molecules are accommodated in the major groove. (C) 1999 Academic Press.