The stability of DNA duplexes is dependent on a complex array of hydrogen bonding among amino and carbonyl groups of the heteroaromatic bases and surrounding water molecules, as well as base stacking interactions. Duplex stability can be significantly increased by adding a further hydrogen bond to a base pair, for example by modifying the regular A-T base pair containing two hydrogen bonds with the 2-amino-A-T base pair containing three hydrogen bonds. Another popular strategy is to use a hydrophobic natural or unnatural modification to displace water molecules from the duplex to generate a stabilizing effect. Examples of this strategy are the use of 5-Me-dC or 5-propynyl-dU. With three hydrogen bonds, the C-G base pair has a big effect on duplex stability. A strategy to normalize the effects of C-G and A-T base pairing is to destabilize the C-G base pair to the same strength as the A-T base pair by partially blocking one hydrogen bond using N4-Et-C.