Cryptate binding energies towards high throughput chelator design: metadynamics ensembles with cluster-continuum...

A tiered forcefield/semiempirical/meta-GGA pipeline together with a thermodynamic scheme designed with error cancellation in mind was developed to calculate binding energies of [2.2.2] cryptate complexes of mono- and divalent cations. Stable complexes of Na, K, Rb, Ca, Zn and Pb were generated, revealing consistent cation-N lengths but highly variable cation-O lengths and an amine stacking mechanism potentially augmenting the cation size selectivity. Metadynamics, used for searching the high-dimensional potential energy surface, together with a cluster-continuum model for affordable - yet accurate - solvation modeling, enabled the discovery of more stable geometries than those previously reported. Similar solvation energy curve shapes for lone vs. coordinated ions enabled rapid solvation convergence via the cancellation of errors stemming from finite cluster sizes. An R² of 0.850 vs. experimental aqueous binding energies was obtained, validating this scheme as the backbone of a high-throughput workflow for chelator design.