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Abstract:
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, DGHyd , for amino acids with alkyl side
chains and with 1 to 6 –CH!–CF side chain substitutions. Fluorination changes DGHyd by −1.5 to +2 kcal mol−1, but the number of
fluorines is a poor predictor of hydrophobicity. Changes in DGHyd 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.