Ion-Hydroxyl Interactions: From High-Level Quantum Benchmarks to Transferable Polarizable Force Fields

Abstract

Ion descriptors in molecular mechanics models are calibrated against reference data on ion-water interactions. It is then typically assumed that these descriptors will also satisfactorily describe interactions of ions with other functional groups, such as those present in biomolecules. However, several studies now demonstrate that this transferability assumption produces, in many different cases, large errors. Here we address this issue in a representative polarizable model and focus on transferability of cationic interactions across alcohols that, like water, also use hydroxyls for coordination. We obtain gas phase reference data from vdW-corrected DFT after benchmarking against “gold-standard” diffusion Monte Carlo and CCSD(T) methods. Taken together with experimental condensed phase data, the collected reference energies inform us that the original polarizable model yields large water -> alcohol transferability errors - the RMS and maximum errors are greater than 4.5 and 10 kcal/mol, respectively. These errors are, nevertheless, systematic in that ion-alcohol interactions are over-stabilized, and systematic errors typically imply that some essential physics is either missing or misrepresented. A comprehensive analysis shows that when both low and high-field responses of ligand dipole polarization are described accurately, then transferability improves significantly - the RMS and maximum errors in the gas phase reduce, respectively, to 0.9 and 2.5 kcal/mol. Condensed phase transfer free energies also improve, as the RMS error decreases from 8.9 to 6.6 kcal/mol, however, the error still remains systematic, which we attribute to the parameterization in long range electrostatics. Overall, this work demonstrates a rational approach to boosting transferability of ionic interactions that will be applicable broadly to improving other polarizable and non-polarizable models.