A family of nanoparticles has been fabricated featuring cationic amino acid-based side chains. This controlled surface modification provides a tool to investigate the effect of various non-covalent interactions at the nanoparticle-DNA interface. The binding affinities of these nanoparticles towards DNA were determined using fluorescence, exhibiting more than threefold modulation in binding a 37-mer DNA strand. The secondary structure of the DNA strand was distorted upon nanoparticle binding, with the extent of distortion dependent on the structure of amino acid side chain.