Variable temperature H-1 NMR studies of the host-guest complex [Mo16O16S16(OH)(16)(H2O)(4)(PDA)(2)](4-) (1; PDA(2-) = phenylenediacetate) previously carried out in D2O have revealed a complex behavior in solution, involving a gliding motion of both parallel phenyl rings of the PDA(2-) ligands. In the present work, we present new NMR spectra carded out in the aprotic solvent CD3CN, which allow the observation of the proton signals associated with the bridging hydroxo groups of the inorganic host. The new spectra provide detailed information about the concerted reorganization of the guest components, that is, PDA(2-) and water molecules. The existence of an equilibrium between two distinct isomers differing in the linking mode between the inorganic host and the two equivalent PDA(2-) ligands is evidenced. This equilibrium appears strongly dependent upon the temperature, leading to a complete inversion of the distribution between 300 and 226 K. The thermodynamic data related to the isomerization reaction have been determined (Delta H-r = -50.5 kJ mol(-1) and Delta S-r = -215 J mol(-1) K-1). Furthermore, at low temperature, one of the isomers exists in two conformations, only differing in the H-bond network involving the inner water molecules, Density functional theory calculations were carded out to push ahead the interpretations obtained from experiment, identify the isomers of 1, and specify the role and the positions of the guest water molecules. Among the various structures that have been calculated for 1, three fall in a narrow energy range and should correspond to the species characterized by variable-temperature H-1 NMR experiments in CD3CN. Finally, this study shows how the internal disposition of the ligands affects the ellipticity of the Mo-16 ring which varies from one isomer to the other in the 0.73-1 range and highlights solvation of the ring as one of the key parameters for the conformational design of these flexible host-guest systems.