Variable-Temperature Nmr Spectroscopy, Conformational Analysis, And Thermodynamic Parameters Of Cyclic Adenosine 5 '-Diphosphate Ribose Agonists And Antagonists

Cyclic adenosine 5'-diphosphate ribose (cADPR) is a ubiquitous Ca2+-treleasing second messenger. Knowledge of its conformational landscape is an essential tool for unraveling the structure activity relationship (SAR) in cADPR Variable-temperature H-1 NMR spectroscopy, in conjunction with PSEUROT and population analyses, allowed us to determine the conformations and thermodynamic parameters of the furanose rings, gamma-bonds (C4'-C5'), and ss-bonds (C5'-O5') in the cADPR analogues 2'-deoxy-cADPR, 7-deaza-cADPR, and 8-bromo-cADPR A significant finding was that, although the analogues are similar to each other and to cADPR itself in terms of overall conformation and population (Delta G degrees), there were subtle yet important differences in some of thermodynamic properties (Delta H degrees, Delta S degrees) associated with each of the conformational equilibria. These differences prompted us to propose a model for cADPR in which the interactions between the A2'-N3, A5 ''-N3, and H2-R5' atoms serve to fine-tune the N-glycosidic torsion angles (chi).