'Strain effect' descriptors for ATP and ADP derivatives with modified phosphate groups

Semiempirical AM1 calculations were carried out for quantum chemically optimized conformations of ATP and ADP and their modified phosphate derivatives with the oxygen atoms intervening between phosphorus atoms substituted by imido or methylene groups or the double-bonded oxygen atoms substituted by sulfur. In addition to the calculation of conventional geometric and energetic parameters, the effect of these substitutions was quantified in terms of conformational 'strain energy'. The latter has been defined as the energy of transformation of the parent nucleotide (ATP or ADP) from the optimum conformation to the conformation optimized for its phosphate-modified analog. The results of calculations revealed that conformational 'strain' of phosphate-modified nucleotides depends not only on the nature of the substituent but also on its position. The respective effect had the largest magnitude when the substitution was made between two terminal phosphorus atoms. Given that the 'strain energy' characterizes the geometrical aspects of the interaction of nucleotide molecules with receptors and enzymes, an attempt was made to correlate it with the corresponding biological activities. Such correlation was significant in the case of highly specific binding sites for universal ligands like ATP.