Dynamic simulations of 13 TATA variants refine kinetic hypotheses of sequence/activity relationships

Xiaoliang Qian, Daniel Strahs, Tamar Schlick

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)681-703
Number of pages23
JournalJournal of Molecular Biology
Volume308
Issue number4
DOIs
StatePublished - 2001

Fingerprint

TATA-Box Binding Protein
DNA
Base Pairing
N,N-dimethyl-3,3-diphenyl-1-methylallylamine
Water
Eukaryota
Carrier Proteins
Theoretical Models
Research

Keywords

  • Flexibility
  • Sequence-dependent bending
  • TATA variants
  • TBP
  • Transcriptional activity

ASJC Scopus subject areas

  • Virology

Cite this

Dynamic simulations of 13 TATA variants refine kinetic hypotheses of sequence/activity relationships. / Qian, Xiaoliang; Strahs, Daniel; Schlick, Tamar.

In: Journal of Molecular Biology, Vol. 308, No. 4, 2001, p. 681-703.

Research output: Contribution to journalArticle

@article{ba6ea5ca99bb404f954ca3b75e0ba224,
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.",
keywords = "Flexibility, Sequence-dependent bending, TATA variants, TBP, Transcriptional activity",
author = "Xiaoliang Qian and Daniel Strahs and Tamar Schlick",
year = "2001",
doi = "10.1006/jmbi.2001.4617",
language = "English (US)",
volume = "308",
pages = "681--703",
journal = "Journal of Molecular Biology",
issn = "0022-2836",
publisher = "Academic Press Inc.",
number = "4",

}

TY - JOUR

T1 - Dynamic simulations of 13 TATA variants refine kinetic hypotheses of sequence/activity relationships

AU - Qian, Xiaoliang

AU - Strahs, Daniel

AU - Schlick, Tamar

PY - 2001

Y1 - 2001

N2 - 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.

AB - 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.

KW - Flexibility

KW - Sequence-dependent bending

KW - TATA variants

KW - TBP

KW - Transcriptional activity

UR - http://www.scopus.com/inward/record.url?scp=0034972522&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0034972522&partnerID=8YFLogxK

U2 - 10.1006/jmbi.2001.4617

DO - 10.1006/jmbi.2001.4617

M3 - Article

VL - 308

SP - 681

EP - 703

JO - Journal of Molecular Biology

JF - Journal of Molecular Biology

SN - 0022-2836

IS - 4

ER -