<div><div><div><p>Fluorination can dramatically improve the thermal and proteolytic stability of proteins and their enzymatic activity. Key to the impact of fluorination on protein properties is the hydrophobicity of fluorinated amino acids. We use molecular dynamics simulations, together with a new fixed-charge, atomistic force field, to quantify the changes in hydration free energy for amino acids with alkyl side chains and with 1 to 6 –CH to –CF side chain substitutions. Fluorination changes the hydration free energy by 1.5 to +2 kcal mol<sup>-</sup>1, but the number of fluorines is a poor predictor of hydrophobicity. Changes in hydration free energy reflect two main contributions: i) fluorination alters side chain-water interactions; we identify a crossover point from hydrophilic to hydrophobic fluoromethyl groups which may be used to estimate the hydrophobicity of fluorinated alkyl side-chains; ii) fluorination alters the number of backbone-water hydrogen bonds via changes in the relative side chain-backbone conformation. Our results offer a road map to mechanistically understand how fluorination alters hydrophobicity of (bio)polymers.</p></div></div></div>
Unexpected Trends in the Hydrophobicity of Fluorinated Amino Acids Reflect Competing Changes in Polarity and Conformation