THE ROLE OF INTRAMOLECULAR HYDROGEN-BONDING AS A DETERMINANT OF THE CONFORMATIONAL PROFILES OF CGMP AND CAMP

Computational chemical studies using the AMI semiempirical method and Hartree-Fock calculations with the STO-3G basis set using the AMI structures have been performed on the cyclic nucleotides adenosine 3',5'-cyclic monophosphate (cAMP), guanosine 3',5'-cyclic monophosphate (cGMP), and model compounds. Consistent with earlier experimental and computational studies, cGMP is expected to prefer the syn conformation of the purine/sugar portions, while cAMP prefers the anti conformation. The present studies implicate an intramolecular hydrogen bond, between a hydrogen atom of the C2-amine of the purine and the axial oxygen atom of the cyclic phosphate, in increasing the relative stability of the syn conformation of cGMP. Analysis of the energetics and molecular electrostatic potentials of model compounds and model complexes reveals that the substituent at the C6 carbon atom and the phosphate ring conformation play critical roles in stabilizing this interaction. These conformational profiles along with tautomeric characteristics may help develop hypotheses to explain selectivity for binding to and activation of proteins by the cyclic nucleotides. © 1990, American Chemical Society. All rights reserved.