jo7b02749_si_001.pdf (2.59 MB)

Variable-Temperature NMR Spectroscopy, Conformational Analysis, and Thermodynamic Parameters of Cyclic Adenosine 5′-Diphosphate Ribose Agonists and Antagonists

Download (2.59 MB)
journal contribution
posted on 24.01.2018, 00:00 by Sarah-Marie Saatori, Tanner J. Perez, Steven M. Graham
Cyclic adenosine 5′-diphosphate ribose (cADPR) is a ubiquitous Ca2+-releasing second messenger. Knowledge of its conformational landscape is an essential tool for unraveling the structure–activity relationship (SAR) in cADPR. Variable-temperature 1H NMR spectroscopy, in conjunction with PSEUROT and population analyses, allowed us to determine the conformations and thermodynamic parameters of the furanose rings, γ-bonds (C4′–C5′), and β-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 (ΔG°), there were subtle yet important differences in some of thermodynamic properties (ΔH°, ΔS°) 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 (χ).