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Issue 4, 2019
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Unexpected trends in the hydrophobicity of fluorinated amino acids reflect competing changes in polarity and conformation

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

Graphical abstract: Unexpected trends in the hydrophobicity of fluorinated amino acids reflect competing changes in polarity and conformation

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Publication details

The article was received on 13 Nov 2018, accepted on 03 Jan 2019 and first published on 04 Jan 2019


Article type: Paper
DOI: 10.1039/C8CP07025C
Citation: Phys. Chem. Chem. Phys., 2019,21, 2029-2038
  • Open access: Creative Commons BY license
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    Unexpected trends in the hydrophobicity of fluorinated amino acids reflect competing changes in polarity and conformation

    J. R. Robalo and A. Vila Verde, Phys. Chem. Chem. Phys., 2019, 21, 2029
    DOI: 10.1039/C8CP07025C

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