Protein crystallography and biochemical assays reveal that the organometallic drug, [Ru(eta(6)-p-cymene)Cl-2(pta)] (RAPTA-C), preferentially binds to nucleosomal histone proteins in chromatin. To better understand the binding mechanism we report here a mass spectrometric-based competitive binding study between a model peptide from the acidic patch region of the H2A histone protein (the region where RAPTA-C is known to bind) and an oligonucleotide. In contrast to the protein crystallography and biochemical assays, RAPTA-C preferentially binds to the oligonucleotide, confirming that steric factors, rather than electronic effects, primarily dictate binding of RAPTA-C to histone proteins within the nucleosome.