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Evaluation of binding selectivities and affinities of platinum-based quadruplex interactive complexes by electrospray ionization mass spectrometry.

ABSTRACT: The quadruplex binding affinities and selectivities of two large pi-surface Pt(II) phenanthroimidazole complexes, as well as a smaller pi-surface platinum bipyridine complex and a larger Ru(II) complex, were evaluated by electrospray ionization mass spectrometry. Circular dichroism (CD) spectroscopy was used to determine the structures of various quadruplexes and to study the thermal denaturation of the quadruplexes in the absence and presence of the metal complexes. In addition, chemical probe reactions with glyoxal were used to monitor the changes in the quadruplex conformation because of association with the complexes. The platinum phenanthroimidazole complexes show increased affinity for several of the quadruplexes with elongated loops between guanine repeats. Quadruplexes with shorter loops exhibited insubstantial binding to the transition metal complexes. Similarly binding to duplex and single strand oligonucleotides was low overall. Although the ruthenium-based metal complex showed somewhat enhanced quadruplex binding, the Pt(II) complexes had higher quadruplex affinities and selectivities that are attributed to their square planar geometries. The chemical probe reactions using glyoxal indicated increased reactivity when the platinum phenanthroimidazole complexes were bound to the quadruplexes, thus suggesting a conformational change that alters guanine accessibility.

SUBMITTER: Pierce SE

PROVIDER: S-EPMC2725001 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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Evaluation of binding selectivities and affinities of platinum-based quadruplex interactive complexes by electrospray ionization mass spectrometry.

Pierce Sarah E SE Kieltyka Roxanne R Sleiman Hanadi F HF Brodbelt Jennifer S JS

Biopolymers 20090401 4

The quadruplex binding affinities and selectivities of two large pi-surface Pt(II) phenanthroimidazole complexes, as well as a smaller pi-surface platinum bipyridine complex and a larger Ru(II) complex, were evaluated by electrospray ionization mass spectrometry. Circular dichroism (CD) spectroscopy was used to determine the structures of various quadruplexes and to study the thermal denaturation of the quadruplexes in the absence and presence of the metal complexes. In addition, chemical probe ...[more]

PMID: 19117031

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Project description:We present the first comprehensive capillary electrophoresis electrospray ionization mass spectrometry (CESI-MS) analysis of post-translational modifications derived from H1 and core histones. Using a capillary electrophoresis system equipped with a sheathless high-sensitivity porous sprayer and nano-liquid chromatography electrospray ionization mass spectrometry (nano-LC-ESI-MS) as two complementary techniques, we characterized H1 histones isolated from rat testis. Without any pre-separation of the perchloric acid extraction, a total of 70 different modified peptides, including 50 phosphopeptides, were identified in the rat linker histones H1.0, H1a-H1e, and H1t. Out of the 70 modified H1 histone peptides, 27 peptides could be identified with CESI-MS only, and 11 solely with LC-ESI-MS. Immobilized metal-affinity chromatography enrichment prior to MS analysis yielded a total of 55 phosphopeptides; 22 of these peptides could be identified only by CESI-MS, and 19 only by LC-ESI-MS, showing the complementarity of the two techniques. We mapped 42 H1 modification sites, including 31 phosphorylation sites, of which 8 were novel sites. For the analysis of core histones, we chose a different strategy. In a first step, the sulfuric-acid-extracted core histones were pre-separated using reverse-phase high-performance liquid chromatography. Individual rat testis core histone fractions obtained in this way were digested and analyzed via bottom-up CESI-MS. This approach yielded the identification of 42 different modification sites including acetylation (lysine and N(α)-terminal); mono-, di-, and trimethylation; and phosphorylation. When we applied CESI-MS for the analysis of intact core histone subtypes from butyrate-treated mouse tumor cells, we were able to rapidly detect their degree of modification, and we found this method very useful for the separation of isobaric trimethyl and acetyl modifications. Taken together, our results highlight the need for additional techniques for the comprehensive analysis of post-translational modifications. CESI-MS is a promising new proteomics tool as demonstrated by this, the first comprehensive analysis of histone modifications, using rat testis as an example.

Dataset Information

Evaluation of binding selectivities and affinities of platinum-based quadruplex interactive complexes by electrospray ionization mass spectrometry.

Publications

Evaluation of binding selectivities and affinities of platinum-based quadruplex interactive complexes by electrospray ionization mass spectrometry.

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