Max Planck Institute for Colloids and Interfaces, Department of Theory & Bio-systems, Science Park, Potsdam 14424, Germany.
Phys Chem Chem Phys. 2019 Jan 23;21(4):2029-2038. doi: 10.1039/c8cp07025c.
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.
氟化可以显著提高蛋白质的热稳定性和蛋白水解稳定性及其酶活性。氟化对蛋白质性质的影响的关键是氟化氨基酸的疏水性。我们使用分子动力学模拟，以及一个新的固定电荷原子力场，来量化具有烷基侧链和 1 到 6 个-CH→-CF 侧链取代的氨基酸的水合自由能变化 ΔGHyd。氟化使 ΔGHyd 变化-1.5 到+2 kcal mol-1，但氟原子的数量并不能很好地预测疏水性。ΔGHyd 的变化反映了两个主要贡献：（i）氟化改变了侧链-水相互作用；我们确定了从亲水性到疏水性氟甲基基团的交叉点，可用于估计氟化烷基侧链的疏水性；（ii）通过相对侧链-主链构象的变化，氟化改变了主链-水氢键的数量。我们的结果为从机械角度理解氟化如何改变（生物）聚合物的疏水性提供了一个路线图。
