title: Dynamic simulations of 13 TATA variants refine kinetic hypotheses of sequence/activity relationships.
abstract: 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 the TATA-box binding protein (TBP). The recent crystallographic study by Burley and co-workers demonstrated the remarkable structural similarity contrasted to different transcriptional activity of 11 TBP/DNA complexes in which the DNAs differed by single base-pairs. By simulating these TATA variants and two other single base-pair 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 by refining kinetic hypotheses on sequence/activity correlations. The 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 features accompany the severe deformation induced by the minor-groove binding protein, which kinks the TATA element at the ends and displaces local water molecules to form stabilizing hydrophobic contacts. Interestingly, the preferred bending direction itself is not a significant predictor of activity disposition, although certain variants (such as wild-type 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, flexibility, and hydration preferences, 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 base-pair DNA variations on DNA motion. Our refined kinetic hypothesis suggests the functional implications of these motions in a kinetic model of TATA/TBP recognition, inviting further theoretical and experimental research.
authors.affiliation: Department of Chemistry and Courant Institute of Mathematical Sciences, New York University and the Howard Hughes Medical Institute, 251 Mercer Street, New York, NY 10012, USA.
authors.forename: X
authors.initials: X
authors.lastname: Qian
authors.forename: D
authors.initials: D
authors.lastname: Strahs
authors.forename: T
authors.initials: T
authors.lastname: Schlick
mesh_terms: D001483:Base Sequence; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D019992:Databases as Topic; D014644:Genetic Variation / Q000235:genetics; D007477:Ions / Q000378:metabolism; D007700:Kinetics; D008958:Models, Molecular; D009038:Motion; D009690:Nucleic Acid Conformation; D018583:Pliability; D017354:Point Mutation / Q000235:genetics*; D012997:Solvents; D013329:Structure-Activity Relationship; D016385:TATA Box / Q000235:genetics*; D035181:TATA-Box Binding Protein; D013816:Thermodynamics; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D014867:Water / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D007477:Ions; D012997:Solvents; D035181:TATA-Box Binding Protein; D014157:Transcription Factors; D014867:Water; D004247:DNA