Document Detail

Microscopic Rearrangement of Bound Minor Groove Binders Detected by NMR.
MedLine Citation:
PMID:  22530735     Owner:  NLM     Status:  Publisher    
Thermodynamic and structural studies are commonly utilized to optimize small molecules for specific DNA interactions and thus, a significant amount of binding data is available. However, the dynamic processes that are involved in minor groove complex formation and maintenance are not fully understood. To help define the processes involved, we have conducted 1D and 2D NMR in conjunction with biosensor-SPR experiments with a variety of compounds and symmetric, as well as asymmetric, AT tract DNA sequences. Surprisingly, the NMR data clearly show exchange between equivalent binding sites for strongly binding compounds like netropsin and DB921 (<italic>K</italic><sub>a</sub> > 10<sup>8</sup> M<sup>-1</sup>) that does not involve dissociation off the DNA. A quantitative analysis of the data revealed that these bound exchange rates are indeed much faster than the macroscopic dissociation rates which were independently determined by biosensor-SPR. Additionally, we could show the existence of at least two 1:1 compound DNA complexes at the same site for the interaction of these compounds with an asymmetric DNA sequence. To explain this behavior we introduced a model in which the ligand is rapidly flipping between two orientations while in close association with the DNA. The ligand reorientation will contribute favorably to the binding entropy. As the potential of minor groove binders to form more than a single complex with asymmetric, as well as symmetric, duplexes is widely unknown, the consequences for binding thermodynamics and compound design are discussed.
Michael Rettig; Markus W Germann; Mohamed A Ismail; Adalgisa Batista-Parra; Manoj Munde; David Withers Boykin; W David Wilson
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-4-24
Journal Detail:
Title:  The journal of physical chemistry. B     Volume:  -     ISSN:  1520-5207     ISO Abbreviation:  -     Publication Date:  2012 Apr 
Date Detail:
Created Date:  2012-4-25     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101157530     Medline TA:  J Phys Chem B     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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