Hydration Thermodynamic Properties of Amino Acid Analogues:  A Systematic Comparison of Biomolecular Force Fields and Water Models

We present an extensive study on hydration thermodynamic properties of analogues of 13 amino acid side chains at 298 K and 1 atm. The hydration free energies ΔG, entropies ΔS, enthalpies ΔH, and heat capacities Δc_P were determined for 10 combinations of force fields and water models. The statistical sampling was extended such that precisions of 0.3, 0.8, 0.8 kJ/mol and 25 J/(mol K) were reached for ΔG, TΔS, ΔH, and Δc_P, respectively. The three force fields used in this study are AMBER99, GROMOS 53A6, and OPLS-AA; the five water models are SPC, SPC/E, TIP3P, TIP4P, and TIP4P-Ew. We found that the choice of water model strongly influences the accuracy of the calculated hydration entropies, enthalpies, and heat capacities, while differences in accuracy between the force fields are small. On the basis of an analysis of the hydrophobic analogues of the amino acid side chains, we discuss what properties of the water models are responsible for the observed discrepancies between computed and experimental values. The SPC/E water model performs best with all three biomolecular force fields.