(231ah) Hydration Free Energies Calculated Using the AMBER ff03 Charge Model for Natural and Unnatural Amino Acids and Multiple Water Models
Accurate interactions with solvent water and its implicit solvent approximations are critical to the success or failure of folding, reﬁning, or designing a protein with state-of-the art methods1-9. We recently developed two new forcefields for post-translational modifications10 and unnatural/modified amino acids11 to enable the modeling, simulation, and design of proteins containing them. Chemical and biochemical modification of amino acids are ubiquitous in nature, with over 400 previously discovered to date12.
In this work13, we assess calculated hydration free energies of natural and unnatural/modified amino acids compared to experimental hydration free energies of corresponding side-chain analogs using the ff0314 charge model. Fine-grid, explicit water multiconfigurational thermodynamic integration15 calculations using two widely used explicit water models (TIP3P16 and TIP4P-Ew17) were performed on 19 natural amino acids and compared with experimental hydration free energies of corresponding side-chain analogs to establish expected accuracy levels for this charge model. Hydration data for side-chain analogs of the natural amino acids were taken from the dataset compiled by Wolfenden18.
Next, parameters we previously derived11 for 17 unnatural amino acids and several new parameters optimized in this work were assessed using the same methodology. We found that the ff03 charge model is correlated with experimental hydration free energies but underestimates the solubilities of several polar natural and unnatural amino acids. That is the calculated hydration free energies were less negative than their experimental values. Overall, we found that our forcefields can rank hydration free energies of non-canonical amino acid side-chain analogs with a root-mean square error of 2.53 and mean absolute error of 2.10 kcal/mol and an R2 of 0.68 for the non-canonical side-chains by utilizing the widely used TIP3P16water model. Comparisons are presented with other forceﬁelds and water models recently presented in the literature for both natural and modiﬁed amino acids showing excellent agreement of our forcefield and the corresponding experimental data.
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