Molecular recognition of polyamides with DNA: A study on the strong binding of f-ImPyIm to its Cognate DNA, ACGCGT

ORGN 678

Karen Buchmueller, karen.buchmueller@furman.edu1, Suzanna Bailey1, David Matthews1, Janna Register, jregiste@erskine.edu2, Chrystal D. Bruce, cbruce@erskine.edu2, Caroline O'Hare3, John Hartley3, Binh Nguyen4, David Wilson4, and Moses Lee, lee@hope.edu5. (1) Chemistry, Furman University, 3300 Poinsett Hwy, Greenville, SC 29613, (2) Department of Chemistry, Erskine College, 2 Washington Street, Due West, SC 29639, (3) Oncology, Royal Free & University College Medical School, 91 Riding House Street, London, W1W 7BS, United Kingdom, (4) Department of Chemistry, Georgia State University, 50 Decatur St, Atlanta, GA 30303, (5) Department of Chemistry, Hope College, Natural Sciences Division, 35E. 12th. Street, Holland, MI 49422
The tri-heterocyclic pyrrole-imidazole polyamide, f-ImPyIm, binds its cognate DNA sequence, ACGCGT, with a better affinity than the natural polyamide, Distamycin A binds to its cognate, A3T3 (2e8 and 2e7 M-1, respectively). Interestingly, f-PyImIm, a structural isomer of f-ImPyIm, exhibits weak binding to its cognate DNA, ACCGGT (8e5 M-1). The wide range of binding affinities of these polyamides for their respective cognate sequences has led to the formulation of a "language," where the -ImPy- central core associates more strongly to DNA than -PyPy-, -ImPy-, and -ImIm-, in descending order. The focus of the present study is to probe the physical basis for the strong affinity of f-ImPyIm for DNA. DNase I footprinting studies were used to confirm the specificity of f-ImPyIm for ACGCGT, within a larger DNA fragment (~100 bp), which contains competing sites. These studies confirmed that f-ImPyIm has superior sequence selectivity over Distamycin A and f-PyImIm. The effects of cations and osmolytes on the binding of f-ImPyIm and f-PyImIm with their respective cognate and flanking-modified sequences were studied by DNA thermal melts and isothermal microcalorimetry (ITC). The thermodynamic contributions, including changes in heat capacity, were elucidated using ITC and molecular dynamics studies. In addition, analysis of the dynamic nature of the DNA before and after complex formation was determined using NMR.
 

Lipids, Nucleotides, and Mimetics
1:00 PM-4:20 PM, Thursday, 30 March 2006 Georgia World Congress Center -- C301, Oral

Division of Organic Chemistry

The 231st ACS National Meeting, Atlanta, GA, March 26-30, 2006