Dynamic Simulations of 13 TATA Variants Refine Kinetic Hypotheses on Sequence/Activity Relationships

The fundamental relationship between DNA sequence/deformability and biological function has attracted numerous experimental and theoretical studies. A classic prototype system used for such studies in eukaryotes is the complex between the TATA element transcriptional regulator and TBP. The recent crystallographic study of Burley and co-workers demonstrated the remarkable contrast between the structural similarity and different transcriptional activity of 11 different TBP/DNA complexes (in which the DNAs differed by single bps from each other). By simulating these TATA variants and two other single bp variants that were not crystallizable, we uncover sequence-dependent structural, energetic, and flexibility properties that tailor TATA elements to TBP interactions, complementing many previous studies. Such factors that combine to produce favorable elements for TBP activity include overall flexibility; minor groove widening, as well as roll, rise, and shift increases at the ends of the TATA element; untwisting within the TATA element accompanied by large roll at the TATA element ends; and relatively low maximal water densities around the DNA. These factors work with the severe deformation induced by the minor-groove binding protein, which kinks the TATA element at the ends and displaces local waters to form stabilizing hydrophobic contacts. Interestingly, the preferred bending direction itself is not a significant predictor of activity disposition, although certain variants (such as wildtype AdMLP, 5'-TATA4G-3', and inactive A29, 5'-TA6G-3') exhibit large preferred bends in directions consistent with their activity or inactivity (major groove and minor groove bends, respectively). These structural patterns, identified here and connected to a new crystallographic study of a larger group of DNA variants than reported to date, highlight the profound influence of single-bp DNA variations on structure, flexibility, and hydration preferences and the evolutionary complementarity between DNAs and proteins in binding and activity.

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