Density-functional theory was used to study the hydrogen-bonding properties of a series of modified purines that contain unusual glycosylation positions. These. unique molecules have been previously studied experimentally for their ability to behave as universal nucleobases, which must bind with an equal affinity to all natural DNA bases. The thermodynamics and kinetics for rotation about the glycosidic bond are considered since two hydrogen-bonding faces must be readily available for these molecules to bind with all natural nucleobases. The binding energies between modified and natural bases are also calculated. The present study provides support for the universal properties of some modified nucleobases and offers potential explanations for why other modifications do not bind indiscriminately. (c) 2005 Elseiver B.V. All rights reserved.