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Conformational energies and equilibria of cyclic dinucleotides in vacuo and in solution: computational chemistry vs. NMR experiments.

Performance of computational methods in modelling cyclic dinucleotides - an important and challenging class of compounds - has been evaluated by two different benchmarks: (1) gas-phase conformational energies and (2) qualitative agreement with NMR observations of the orientation of the χ-dihedral angle in solvent. In gas-phase benchmarks, where CCSD(T) and DLPNO-CCSD(T) methods have been used as the reference, most of the (dispersion corrected) density functional approximations are accurate enough to justify prioritizing computational cost and compatibility with other modelling options as the criterion of choice. NMR experiments of 3'3'-c-di-AMP, 3'3'-c-GAMP, and 3'3'-c-di-GMP show the overall prevalence of the anti-conformation of purine bases, but some population of syn-conformations is observed for guanines. Implicit solvation models combined with quantum-chemical methods struggle to reproduce this behaviour, probably due to a lack of dynamics and explicitly modelled solvent, leading to structures that are too compact. Molecular dynamics simulations overrepresent the syn-conformation of guanine due to the overestimation of an intramolecular hydrogen bond. Our combination of experimental and computational benchmarks provides "error bars" for modelling cyclic dinucleotides in solvent, where such information is generally difficult to obtain, and should help gauge the interpretability of studies dealing with binding of cyclic dinucleotides to important pharmaceutical targets. At the same time, the presented analysis calls for improvement in both implicit solvation models and force-field parameters.