The mechanics of minor groove width variation in DNA, and its implications for 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 affected by movement of the bases, which for example may enforce groove compression or expansion through a rolling action of the adjacent base-pairs. Moreover, the sugar-phosphate backbone can also undergo limited movement, independently of the bases, which will affect the groove shape. We have examined how the movement of the sugar-phosphate backbone may affect the minor groove width for a fixed base geometry. In agreement with earlier studies, the sugar-phosphate backbone is found to have a certain degree of conformational flexibility in A and B-like helices, and we note a comparable freedom even in the highly curved TATA element of the TATA-binding protein/DNA complex. Phosphate mobility is highly anisotropic in all cases with favoured directions that can significantly change the groove width, independent of any changes in base geometry. We describe how the movement of the sugar-phosphate backbone may affect the accommodation of drugs and proteins in the minor groove, and we present a co-ordinate scheme which emphasises the groove adjustments associated with ligand binding. The observations have implications for the related problem of how cognate molecules are accommodated in the major groove.