Design and binding of a distamycin A analog to d(CGCAAGTTGGC).cntdot.d(GCCAACTTGCG): synthesis, NMR studies, and implications for the design of sequence-specific minor groove binding oligopeptides

Dwyer, Tammy J.; Geierstanger, Bernhard H.; Bathini, Yadagiri; Lown, J. William; Wemmer, David E.

doi:10.1021/ja00041a001

Cited by 91 publications

(60 citation statements)

References 3 publications

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“…Considerable X-ray and NMR structural data exist to support the formation of Im-N3 to G-NH2 hydrogen bonds for the Im/Py pair in the 2:1 motif. 12,26,27,47 In the 1:1 complex, we find a specific oriented hydrogen bond from Im-N3 to G-NH2. In fact, the ImPy sections of the polyamide presented here are structurally similar to the compounds originally synthesized by Lown and co-workers.…”

Section: The Lexitropsin Modelmentioning

confidence: 78%

Structure of a β-Alanine-linked Polyamide Bound to a Full Helical Turn of Purine Tract DNA in the 1:1 Motif

Urbach

Love

Ross

et al. 2002

Journal of Molecular Biology

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Polyamides composed of N-methylpyrrole (Py), N-methylimidazole (Im) and N-methylhydroxypyrrole (Hp) amino acids linked by b-alanine (b) bind the minor groove of DNA in 1:1 and 2:1 ligand to DNA stoichiometries. Although the energetics and structure of the 2:1 complex has been explored extensively, there is remarkably less understood about 1:1 recognition beyond the initial studies on netropsin and distamycin. We present here the 1:1 solution structure of ImPy -b -Im-b -ImPy -b-Dp bound in a single orientation to its match site within the DNA duplex 5 0 -CCAAAGAGAAGCG-3 0 ·5 0 -CGCTTCTCTTTGG-3 0 (match site in bold), as determined by 2D 1 H NMR methods. The representative ensemble of 12 conformers has no distance constraint violations greater than 0.13 Å and a pairwise RMSD over the binding site of 0.80 Å . Intermolecular NOEs place the polyamide deep inside the minor groove, and oriented N -C with the 3 0 -5 0 direction of the purine-rich strand. Analysis of the high-resolution structure reveals the ligand bound 1:1 completely within the minor groove for a full turn of the DNA helix. The DNA is B-form (average rise ¼ 3.3 Å , twist ¼ 388) with a narrow minor groove closing down to 3.0-4.5 Å in the binding site. The ligand and DNA are aligned in register, with each polyamide NH group forming bifurcated hydrogen bonds of similar length to purine N3 and pyrimidine O2 atoms on the floor of the minor groove. Each imidazole group is hydrogen bonded via its N3 atom to its proximal guanine's exocyclic amino group. The important roles of b-alanine and imidazole for 1:1 binding are discussed.

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Section: The Lexitropsin Modelmentioning

confidence: 78%

Structure of a β-Alanine-linked Polyamide Bound to a Full Helical Turn of Purine Tract DNA in the 1:1 Motif

Urbach

Love

Ross

et al. 2002

Journal of Molecular Biology

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“…However, recent experimental studies carried out by Dwyer et al (12) have shown that the introduction of a G-C base pair in an otherwise A+T-rich region widens the minor groove and allows the accommodation of two Dst molecules. According to the recently reported experimental studies by Dwyer et al (12) …”

Section: Introductionmentioning

confidence: 99%

Relative binding affinities of distamycin and its analog to d(CGCAAGTTGGC).d(GCCAACTTGCG): comparison of simulation results with experiment.

Singh

Wemmer²,

Kollman³

1994

Proc. Natl. Acad. Sci. U.S.A.

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We report here an effort to use molecular dynamics/free energy perturbation methodology to calculate relative binding affinities of two related drugs to DNA. Specifically, we focus on the relative binding free energies of distamycin (Dst) (7), who studied the base specificity ofthe interactions of daunomycin and acridine to DNA. Gago and Richards (8) and Hard and Nilsson (9) have also studied the base specificity of the interactions of netropsin with DNA. To our knowledge, this is the first reported effort to calculate the relative binding free energies of ligands to DNA.One of the difficulties in applying free energy simulations on macromolecular systems is the long simulation times required to sample the possible conformations while maintaining equilibrium at each stage during the perturbation process. At present there is no way to assure that a simulation has been run long enough so that all possible conformations accessible to the system on the path of transformation have been sampled. In addition to sampling, there is the issue of the accuracy of force field parameters employed in these calculations and also several approximations involved in the handling of the long-range nonbonded interactions. Therefore, it is important to gain as much empirical experience with running FEP calculations under different conditions to study and understand the validity ofthe approximations involved in these calculations.The binding of Dst and its variant 2-imidazole distamycin (2-ImD) to DNA represents not only an interesting system to understand DNA-drug interaction but also provides the opportunity to test the FEP methodology. This is because the mutations of the structure are small, involving only the mutation of the van der Waals parameters of N-D -* C-H (where D is the dummy atom) and the partial electrostatic charges of all the atoms on the ligand.Dst, like netropsin, is known to bind specifically to the minor groove of A+T-rich regions of B-DNA. Lavery and Pullman (10) have carried out electrostatic potential calculations and have shown that the minor groove of A+T-rich B-DNA sequence has the lowest negative potential. From this they inferred that the cationic drugs will exhibit binding specificity to the minor groove regions of A+T-rich sequences. The crystal structure of a DNA'Dst complex showed that there is only one molecule bound to the minor groove of an AATT DNA site (11). However, recent experimental studies carried out by Dwyer et al. (12) have shown that the introduction of a G-C base pair in an otherwise A+T-rich region widens the minor groove and allows the accommodation of two Dst molecules. According to the recently reported experimental studies by Dwyer et al. (12)

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“…The concentration of the double-stranded DNA sample was 2.3 mM. The DNA resonances were assigned as described in Chapter 2, and the ligand resonances were assigned as described below (Pelton & Wemmer, 1989;Pelton & Wemmer, 1990b;Dwyer et al, 1992;Mrksich et al, 1992).…”

Section: Synthesis Of Ligands Andmentioning

confidence: 99%

“…Structural studies of complexes of netropsin and distamycin with various DNA oligomers has led to the design of analogs which have been successful in recognizing specific mixed A,T-and G,C-containing sequences (Lown et al, 1986;Wade & Dervan, 1987;Dwyer et al, 1992;Mrksich et al, 1992;Geierstanger et al, 1993;Lee et al, 1993a;Geierstanger et al, 1994a). Most recently an analog has been developed which binds an entirely G,C core site four base pairs long (Geierstanger et al, 1994b).…”

Section: Introductionmentioning

confidence: 99%

“…Several lexitropsin:DNA complexes have been characterized structurally, and have been found to bind in the predicted fashion to their target DNA sites (e.g. Dwyer et al, 1992;Mrksich et al, 1992;Geierstanger et al, 1994a (Kim et al, 1993a;Kim et al, 1993b), LEF-1 (for lymphoid enhancer-binding factor) (Love et al, 1995), SRY (for sex-determining region Y) (Werner et al, 1995), and purine repressor (PurR) (Schumacher et al, 1994). The wide range of sequence specificity, or lack of it, exhibited by these and other minor groove-binding proteins can be better understood in the context of our knowledge of small molecule minor groove binders.…”

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confidence: 99%

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NMR studies of DNA oligomers and their interactions with minor groove binding ligands

Fagan

1996

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Molecules which direct chemistry to a specific DNA sequence could be used as antiviral compounds, diagnostic probes, or molecular biology tools. I studied two ligands in which reactive groups were tethered to a distamycin to increase the sequence specificity 1 of the reactive agent. The DNA cleaving agent netropsin-diazene binds at the predicted DNA site, but the presence of the diazene reduces the affinity and the orientational preference of the ligand compared to distamycin. A tethered ligand containing a 2,3-bis(hydroxymethyl) pyrrole crosslinked to a DNA duplex exhibits many similarities to mitomycin C:DNA complexes. The tether unexpectedly bridges one base pair. These results are important considerations in ligand design, since sometimes ligand binding behavior cannot be predicted from the behavior of the parent molecule.The pairing geometry of cytosine with the highly mutagenic base analog 2-aminopurine has been debated for years. With the use of NMR spectroscopy and selectively 15 N-labeled DNA, the AP«C mispair was found to form a wobble geometry.The structure and stability of this base mispair depend upon the local base sequence.Approved: ., ( -,"_,,,

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Design and binding of a distamycin A analog to d(CGCAAGTTGGC).cntdot.d(GCCAACTTGCG): synthesis, NMR studies, and implications for the design of sequence-specific minor groove binding oligopeptides

Cited by 91 publications

References 3 publications

Structure of a β-Alanine-linked Polyamide Bound to a Full Helical Turn of Purine Tract DNA in the 1:1 Motif

Structure of a β-Alanine-linked Polyamide Bound to a Full Helical Turn of Purine Tract DNA in the 1:1 Motif

Relative binding affinities of distamycin and its analog to d(CGCAAGTTGGC).d(GCCAACTTGCG): comparison of simulation results with experiment.

NMR studies of DNA oligomers and their interactions with minor groove binding ligands

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