Document Detail

Probing sequence-specific DNA flexibility in a-tracts and pyrimidine-purine steps by nuclear magnetic resonance (13)C relaxation and molecular dynamics simulations.
MedLine Citation:
PMID:  23035755     Owner:  NLM     Status:  MEDLINE    
Sequence-specific DNA flexibility plays a key role in a variety of cellular interactions that are critical for gene packaging, expression, and regulation, yet few studies have experimentally explored the sequence dependence of DNA dynamics that occur on biologically relevant time scales. Here, we use nuclear magnetic resonance (NMR) carbon spin relaxation combined with molecular dynamics (MD) simulations to examine the picosecond to nanosecond dynamics in a variety of dinucleotide steps as well as in varying length homopolymeric A(n)·T(n) repeats (A(n)-tracts, where n = 2, 4, or 6) that exhibit unusual structural and mechanical properties. We extend the NMR spin relaxation time scale sensitivity deeper into the nanosecond regime by using glycerol and a longer DNA duplex to slow overall tumbling. Our studies reveal a structurally unique A-tract core (for n > 3) that is uniformly rigid, flanked by junction steps that show increasing sugar flexibility with A-tract length. High sugar mobility is observed at pyrimidine residues at the A-tract junctions, which is encoded at the dinucleotide level (CA, TG, and CG steps) and increases with A-tract length. The MD simulations reproduce many of these trends, particularly the overall rigidity of A-tract base and sugar sites, and suggest that the sugar-backbone dynamics could involve transitions in sugar pucker and phosphate backbone BI ↔ BII equilibria. Our results reinforce an emerging view that sequence-specific DNA flexibility can be imprinted in dynamics occurring deep within the nanosecond time regime that is difficult to characterize experimentally at the atomic level. Such large-amplitude sequence-dependent backbone fluctuations might flag the genome for specific DNA recognition.
Evgenia N Nikolova; Gavin D Bascom; Ioan Andricioaei; Hashim M Al-Hashimi
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-10-18
Journal Detail:
Title:  Biochemistry     Volume:  51     ISSN:  1520-4995     ISO Abbreviation:  Biochemistry     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2013-01-18     Completed Date:  2013-03-19     Revised Date:  2013-11-04    
Medline Journal Info:
Nlm Unique ID:  0370623     Medline TA:  Biochemistry     Country:  United States    
Other Details:
Languages:  eng     Pagination:  8654-64     Citation Subset:  IM    
Department of Chemistry and Biophysics, University of Michigan, 930 North University Avenue, Ann Arbor, MI 48109, USA.
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MeSH Terms
Base Sequence
DNA / chemistry*
Molecular Dynamics Simulation
Nuclear Magnetic Resonance, Biomolecular*
Nucleic Acid Conformation
Nucleotides / chemistry
Purines / chemistry*
Pyrimidines / chemistry*
Grant Support
Reg. No./Substance:
0/Nucleotides; 0/Purines; 0/Pyrimidines; 9007-49-2/DNA; K8CXK5Q32L/pyrimidine; W60KTZ3IZY/purine

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