The contributions from anions and cations from salt are inseparable in their perturbation of molecular systems by experimental and computational methods, rendering it difficult to dissect the effects exerted by the anions and cations individually. Here we investigate the solvation of a small molecule, caffeine, and its perturbation by monovalent salts from various parts of the Hofmeister series. Using molecular dynamics and the energy-representation theory of solvation, we estimate the solvation free energy of caffeine and decompose it into the contributions from anions, cations, and water. We also decompose the contributions arising from the solute-solvent and solute-ions interactions and that from excluded volume, enabling us to pin-point the mechanism of salt. Anions and cations revealed high contrast in their perturbation of caffeine solvation, with the cations salting-in caffeine via binding to the polar ketone groups, while the anions were found to be salting-out via perturbations of water. In agreement with previous findings, the perturbation by salt is mostly anion dependent, with the magnitude of the excluded-volume effect found to be the governing mechanism. The free-energy decomposition as conducted in the present work can be useful to understand ion-specific effects and the associated Hofmeister series.

Department of Physical Chemistry University of Chemistry and Technology Prague CZ 16628 Czech Republic

Division of Chemical Engineering Graduate School of Engineering Science Osaka University Toyonaka Osaka 560 8531 Japan

Division of Theoretical Chemistry Department of Chemistry Lund University Lund SE 221 00 Sweden

Lund Institute for Advanced Neutron and 10 ray Science Lund University Lund Sweden

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Salt Effects on Caffeine across Concentration Regimes