Structure-Activity Relationships for the Affinity of Chaotropic Polyoxometalate Anions towards Proteins

The influence of the composition of chaotropic polyoxometalate (POM) anions on their affinity to biological systems was studied by means of atomistic molecular dynamics (MD) simulations. The variations in the affinity to hen egg-white lysozyme (HEWL) were analyzed along two series of POMs whereby the charge or the size and shape of the metal cluster are modified systematically. Our simulations revealed a quadratic relationship between the charge of the POM and its affinity to HEWL as a consequence of the parabolic growth of POM⋅⋅⋅water interaction with the charge. As the charge increases, POMs become less chaotropic (more kosmotropic) increasing the number and the strength of POM-water hydrogen bonds and structuring the solvation shell around the POM. This atomistic description explains the proportionally larger desolvation energies and less protein affinity for highly charged POMs, and consequently, the preference for moderate charge densities (q/M=0.33). Also, our simulations suggest that POM⋅⋅⋅protein interactions are size-specific. The cationic pockets of HEWL protein show a preference for Keggin-like structures, which display the optimal dimensions (≈1 nm). Finally, we developed a quantitative multidimensional model for protein affinity with predictive ability (r² =0.97; q² =0.88) using two molecular descriptors that account for the charge density (charge per metal atom ratio; q/M) and the size and shape (shape weighted-volume; V_S ).