(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 methods^1-9. 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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