Interrelation between glycosidic torsion, sugar pucker, and backbone conformation in 5'-beta-nucleotides. A 1H and 31P fast Fourier transform nuclear magnetic resonance investigation of the conformation of 8-aza-5'-beta-adenosine monophosphate and 8-aza-5'-beta-guanosine monophosphate.
Hydrogen-1 and phosphorus-31 nuclear magnetic resonance spectra of 5'-AMP, 5'-GMP, 8-aza-5'-GMP, adenosine, 8-aza-adenosine, and guanosine were obtained at biological pH values at a concentration sufficiently low to obtain information regarding their intramolecular solution conformation. The spectra were analyzed by computer simulation. It is shown that all of the above nucleosides and nucleotides have a flexible molecular framework in aqueous solution, 5'-AMP and 5'-GMP showing preference for anti(2-E in equilibrium 3-E)gg-g'g' conformations and the 8-aza analogs showing preference for (syn in equilibrium anti)-(2E in equilibrium 3-E) - g/t-g'g' conformations. In addition, aza substitution causes increase in 3-E sugar populations and in the populations of g'/t' conformers. It is argued that in the 8-aza analogs repulsive electrostatic interactions would prevail between --N (see article) at the 8 position and the negatively charged phosphate group, if the molecule existed in the anti-gg orientation. Such electrostatic repulsions can be relieved by rotating the C(4')--C(5') bond from gg to g/t orientations as well as by torsional variation about the glycosidic linkage from anti to syn conformation. Rotation from anti to syn orientation, for steric and electrostatic reasons, necessitates a simultaneous rotation about the C(4')--C(5') bond from gg to g/t conformation. The observation that the 8-aza substitution in 5'-beta-purine nucleotides cause a depopulation of gg and anti conformers with corresponding increase in the population of g/t and syn orientation seems to support the above thesis. The finding that rotational variation about a bond such as C(4')--C(5') is accompanied by torsional variation about C(5')--O(5') and the glycosidic bonds, as well as changes in the endocyclic torsion angles of the ribose moiety, gives important insight into the engineering of nucleic acid components: even though they in general prefer certain conformations, there is enough flexibility present in their molecular framework, that the entire system can undergo conformational adjustment in response to a perturbation. A conformational basis for the antileukemic effects of 8-aza purines is proposed.
D000241:Adenosine / Q000031:analogs & derivatives; D000249:Adenosine Monophosphate / Q000031:analogs & derivatives*; D001372:Aza Compounds; D001665:Binding Sites; D005583:Fourier Analysis; D006150:Guanine Nucleotides; D006151:Guanosine; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D010759:Phosphorus Isotopes; D013329:Structure-Activity Relationship
D001372:Aza Compounds; D006150:Guanine Nucleotides; D010759:Phosphorus Isotopes; D006151:Guanosine; D000249:Adenosine Monophosphate; D000241:Adenosine