The invention concerns compositions comprising a nucleic acid mimic. The compositions may be used in the diagnosis and treatment of diseases amenable through modulation of nucleic acids which encode proteins that are implicated in disease states. In accordance with preferred embodiments, mimics are comprised of non-naturally occurring backbones to which are appended modified heterocyclic bases. Such bases preferably have sterically bulky substituents 1, 2, or 3 atoms removed from the sites of attachment to the backbone.