Over the years, chromatin drug targeting has become an effective strategy for cancer treatment. In particular, emerging transition metal agents have been shown to act at both nucleosomal DNA and histones levels with high efficiency. The class of ruthenium-based RAPTA (Ru(II), Arene, PTA = 1,3,5-triaza-7-phosphatricyclo[3.3.1.1]decane) compounds interfere with transcription resulting in apoptosis, while gold-based compounds, such as the clinically approved antiarthritic drug Auranofin, have significant antiproliferative properties <i>in vivo</i> and <i>in vitro</i>. Although the anticancer activity can be referred to the ability of these compounds to interfere at the chromatin level, their mechanistic action remains poorly understood. Here, by integrating X-ray crystallography, biochemical assay and extensive molecular dyamics simulations, we reveal a cooperative mechanism of action of Rapta-T (T = Toluene) and Auranofin at the chromatin level. High-resolution crystal structures of the nucleosome core particle (NCP) in complex with the two compounds reveal that the binding occurs at two distal sites on the NCP histone core that are ~35 Å apart. In parallel, biochemical and quantitative ICP/MS experiments show a ~3 fold increased binding of Auranofin when in combination with RAPTA-T, indicating a synergistic effect of the two compounds. By employing microsecond lengths molecular simulations, we clarify at the atomistic level the cooperative binding mechanism, revealing a mechanism of allosteric communication between the ruthenium and gold sites, which occur through a series of subtle conformational changes within the protein framework, transmitted via coupled motions of the histone components. By clarifying the allosteric determinants at molecular level, molecular simulations are key in providing an explanation for an intriguing synergy at cellular level. This opens up new possibilities for epigenetic targeting and suggests that allosteric modulation in nucleosomes may have biological relevance and potential for therapeutic interventions.

Exploring the therapeutic landscape of chromatin via integrative computational modeling: An allosteric regulation from transition metal agents

253rd National Meeting (2017)

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