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DNA Sequence Recognition in the Minor Groove by Crosslinked Polyamides: the Effect of N-Terminal Head Group and Linker Length on Binding Affinity and Specificity

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DNA Sequence Recognition in the Minor Groove by Crosslinked Polyamides: the Effect of N-Terminal Head Group and Linker Length on Binding Affinity and Specificity DNA sequence recognition in the minor groove by crosslinked polyamides: The effect of N-terminal head group and linker length on binding affinity and specificity C. Caroline O’Hare*, Darcy Mack†, Manju Tandon‡, Sanjay K. Sharma‡, J. William Lown‡, Mary L. Kopka†, Richard E. Dickerson†, and John A. Hartley*§ *Cancer Research Campaign Drug–DNA Interactions Research Group, Department of Oncology, Royal Free and University College Medical School, UCL, 91 Riding House Street, London, W1W 7BS, United Kingdom; †Molecular Biology Institute, University of California, Los Angeles, CA 90095; and ‡Department of Chemistry, University of Alberta, Edmonton, AB, Canada T6G 2G2 Contributed by Richard E. Dickerson, November 2, 2001 Development of sequence-reading polyamides or ‘‘lexitropsins’’ has demonstrated that linked polyamides can modulate tran- with comparable DNA-binding affinities to cellular proteins raises scription of specific genes in vitro and in some cell culture the possibility of artificially regulated gene expression. Covalent situations (15–20). linkage of polyamide ligands, with either a hairpin motif or Detailed studies of polyamide binding led to the development crosslinking methylene bridge, has greatly improved binding af- of pairing rules defining optimal combinations of imidazoles and finity by ensuring their side-by-side register. Whereas hairpin pyrroles for binding at predetermined DNA sites (21–23). These polyamides have been investigated extensively, the optimized rules were extended to address the problem of AT͞TA discrim- structure of crosslinked polyamides remains to be determined. This ination through use of a 3-hydroxypyrrole unit for preferential study examines a series of thiazole-imidazole-pyrrole (TIP) mono- thymine recognition, providing the first success in complete mers and crosslinked dimers to evaluate the effects on selectivity sequence recognition in the minor groove of DNA (24–26). and binding affinity of different N-terminal head groups attached Nevertheless, alternative solutions continue to be pursued in an to the leading thiazole ring and differing methylene linker lengths. effort to improve AT͞TA discrimination, which include the Quantitative footprinting of a DNA sequence, containing potential match and mismatch sites for both maximum overlap and one- potential use of thiazole as an adenine discriminator (27–29). residue stagger binding modes, allowed measurement of binding Accurate alignment of the peptide rings alongside each base constants at each putative site. Within an N-terminal amino TIP pair is crucial to providing both sequence specificity and binding series, C7 and C8-linked compounds bound most strongly to these affinity for linked polyamides (6, 30, 31). Optimal length and sites, whereas maximum binding affinity was observed for a C6 geometry of the linkage is required to position both component linker with a formyl head group. A C5 linker gave weak binding ligands in close proximity to the base edges within the minor with either head group. A hydrogen or acetyl head group abro- groove. To achieve this, two types of structures have been gated binding. Binding was confirmed by gel shift analyses. The proposed: a hairpin, whereby the oligopeptides are linked head highest specificity for the maximum overlap site over the one- to tail by using a suitable ‘‘turn peptide’’ (8), and a crosslinked residue stagger was observed with TIP-C7-amino. Selectivity of the or stapled structure, where the central rings of two polyamide leading thiazole was modulated by the head group, with N- ligands are linked via a methylene bridge (7, 12, 32, 33). Whereas terminal formyl TIP exhibiting up to 3-fold specificity for AGT over the binding affinity and selectivity of hairpin polyamides are well TGT, suggesting that N-formyl-thiazole may provide sequence documented (34), the optimum conditions for methylene chain discrimination of adenine over thymine. Moreover, the leading crosslinked polyamides remain to be defined. head group and methylene linker length significantly influences For linked polyamides, two potential DNA-binding modes, an the binding characteristics of crosslinked polyamides. overlap and a staggered orientation, are possible (Fig. 1) (29). In the maximum overlap mode, favored by the hairpin linkage (9, odification of the sequence specificity of DNA minor 35), the absence of an amide on the leading ring holds the Mgroove binders netropsin and distamycin from AT to GC parallel peptide chains in specific register, whereby each ring (1, 2) has led to the development of sequence-reading poly- stacks on an amide of its neighbor. In the one-residue stagger amides or lexitropsins. Strict AT sequence recognition inherent motif, polyamides with a leading amide head group can slip along in the naturally occurring tripyrrole carboxamides has been the peptide chain by one amide yielding an extended reading expanded by replacement of the guanine-excluding pyrrole ring frame. In this binding mode, polyamides also stack ring on with a number of structurally related heterocycles including amide; however, the first amide on each ligand overhangs. This imidazole (3). Following the demonstration that distamycin may sliding of the ligands in relation to each other allows further bind in a 2:1 binding mode (4), oligopeptides containing imida- separation of the charged tails, reducing electrostatic repulsion zole were found also to bind cooperatively in this motif to GC by maximizing the distance between the charges. tracts (5, 6). In this report, we present a detailed study on the effect of the The current generation of polyamides binds as antiparallel N-terminal head group and methylene linker length on the dimers to opposite strands of the minor groove with each binding affinity and specificity of a series of thiazole-imidazole- constituent peptide ring contacting an individual nucleotide base. Covalent linkage of the two component oligopeptides has produced sequence-reading ligands of improved binding affinity Abbreviation: TIP, thiazole-imidazole-pyrrole. (7–13). As a consequence, synthesis of small molecules capable §To whom reprint requests should be addressed. E-mail: [email protected]. of DNA sequence discrimination with equivalent binding affin- The publication costs of this article were defrayed in part by page charge payment. This ities to those of DNA-binding proteins raises the possibility of article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. artificial regulation of gene expression (14). Indeed, recent work §1734 solely to indicate this fact. 72–77 ͉ PNAS ͉ January 8, 2002 ͉ vol. 99 ͉ no. 1 www.pnas.org͞cgi͞doi͞10.1073͞pnas.012588799 Downloaded by guest on September 26, 2021 in 10 mM Tris, pH 7.0͞1 mM EDTA͞50 mM KCl͞1mM ͞ ͞ MgCl2 0.5 mM DTT 20 mM Hepes at room temperature for 30 min in a total volume of 50 ␮l. Cleavage was initiated by the addition of the drug-treated sample to 2 ␮l (0.1 unit) DNase I diluted in ice-cold 10 mM Tris, pH 7.0, from a stock solution (1 ͞␮ ␮ ͞ unit l, Promega) and 1 l of a solution of 250 mM MgCl2 250 mM CaCl2. The reactions were performed at room temperature and stopped after 3 min by the addition of 100 ␮l of a stop mix containing 200 mM NaCl͞30 mM EDTA, pH 8͞1% SDS. The Fig. 1. Binding motifs of TIP. The box indicates which rings are side by side cleavage products were phenol͞chloroform extracted and etha- in the minor groove. (a) Maximum overlap motif. Th, thiazole; Im, imidazole; ␮ ͞ Py, pyrrole. The equal sign signifies an amide, and the plus sign signifies the nol precipitated in the presence of 1 l of glycogen (20 mg ml, charged tail. In the maximum overlap motif, the rings stack ring-on-amide. Roche Diagnostics), washed once in 80% ethanol and lyophilized The DNA target sequence is indicated in capital letters, and the charged tails dry. The samples were resuspended in formamide loading dye, prefer adenine or thymine, a͞t. (b) One residue stagger motif. This motif denatured for 5 min at 90°C, cooled on ice, and electrophoresed requires a leading amide shown in parentheses. Here, the polyamides slip at 2,000 V for2hona6%acrylamide denaturing gel (Sequagel, relative to the maximum overlap, still stacking ring on amide, but moving the National Diagnostics). The gels were dried under vacuum at charged tails further apart. The one residue stagger motif has a longer reading 80°C and exposed to film for 24 h (X-Omat, Kodak). Densitom- frame but still preserves the same number of ring-on-amide interactions. etry was carried out on a Bio-Rad GS-670 imaging densitometer. Equilibrium association constants were determined for target- pyrrole (TIP) crosslinked polyamides (Fig. 2) by using quanti- binding sites for each polyamide (36–39). Volume integrations of five target sites and a reference site allowed the apparent DNA tative DNase I footprinting and gel shift analyses. ␪ target site saturation, app, to be calculated for each concentra- Materials and Methods tion of ligand using the following equation: Quantitative DNase I Footprinting. Ј 32 A 355-bp 5 P-labeled PCR ␪ ϭ 1 Ϫ ͑I ͞I ͒͑͞I ͞I ͒, [1] fragment was generated from the long terminal repeat region of app tot ref o tot o ref plasmid pBSFIV34TF10, kindly provided by Tom Phillips (Vac- where Itot and Iref correspond to the integrated volumes of the cine Research Institute, San Diego, CA), using standard proto- target and reference sites, respectively. I0tot and I0ref are the cols. The labeled fragment was purified by agarose gel electro- integrated volumes for those sites in the absence of polyamide. phoresis and isolated by using a Bio101 kit according to the The data were fitted to a Langmuir binding model (Eq. 2), where manufacturer’s instruction. Polyamides (prepared as in ref. 33) [L]tot is the total polyamide concentration, Ka is the equilibrium Ј ␪ ␪ were incubated with 1,000 cps of 5 single end-labeled fragment association constant, and min and max are the site-saturation values when the site is unoccupied or saturated, respectively.
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