Structural Bioinformatics, BIOTEC TU Dresden, Tatzberg 47-51, 01307 Dresden, Germany.
J Phys Chem B. 2009 Dec 24;113(51):16400-8. doi: 10.1021/jp906402b.
Noncanonical amino acids with newly designed side-chain functionalities represent powerful tools to improve structural, biological, and pharmacological properties of peptides and proteins. In this context, fluorinated amino acids have increasingly gained importance. Despite the current wide use of fluorination in protein engineering, the basic properties of fluorine in protein environments are still not completely understood. Our aim has been to characterize the physicochemical properties of fluorinated amino acids by using quantum mechanics (QM) and molecular dynamics (MD) approaches. We have analyzed geometry, charges, and hydrogen bonding abilities of several ethane fluorinated derivatives at different QM theory levels and have used them as simplified models for fluorinated amino acid side chains. We have parametrized four fluorinated L-amino acids for the AMBER ff94/99 force field: 4-monofluoroethylglycine (MfeGly), 4,4-difluoroethylglycine (DfeGly), 4,4,4-trifluoroethylglycine (TfeGly), and 4,4-difluoropropylglycine (DfpGly). We have characterized them in terms of molecular volumes, conformational preferences, and hydration properties. The obtained results illustrate that fluorine and hydrogen atoms of fluoromethyl groups could be potential acceptors or donors of weak hydrogen bonds in protein environments. Hydration of the studied fluorinated amino acids was found to be more favorable than for their nonfluorinated analogues, and hydrophobicity was observed to increase with the number of fluorine atoms, which is in accordance with the experimental retention times we obtain for these amino acids. This study broadens our understanding of the properties of fluorine within protein environments, which is important to exploit the full potential of fluorine's unique properties for applications in the field of protein engineering.
具有全新设计的侧链功能的非天然氨基酸是改善肽和蛋白质结构、生物学和药理学性质的有力工具。在这方面，氟化氨基酸的重要性日益增加。尽管目前在蛋白质工程中广泛使用氟化，但蛋白质环境中氟的基本性质仍不完全清楚。我们的目的是通过使用量子力学 (QM) 和分子动力学 (MD) 方法来表征氟化氨基酸的物理化学性质。我们分析了几种乙烷氟化衍生物在不同 QM 理论水平下的几何形状、电荷和氢键能力，并将其用作氟化氨基酸侧链的简化模型。我们已经为 AMBER ff94/99 力场参数化了四个氟化 L-氨基酸：4-单氟乙基甘氨酸 (MfeGly)、4,4-二氟乙基甘氨酸 (DfeGly)、4,4,4-三氟乙基甘氨酸 (TfeGly) 和 4,4-二氟丙基甘氨酸 (DfpGly)。我们从分子体积、构象偏好和水合性质方面对它们进行了表征。所得结果表明，氟甲基上的氟和氢原子可能是蛋白质环境中弱氢键的潜在供体或受体。研究中氟化氨基酸的水合作用比其非氟化类似物更有利，并且随着氟原子数的增加疏水性增加，这与我们为这些氨基酸获得的实验保留时间一致。这项研究拓宽了我们对蛋白质环境中氟性质的理解，这对于充分利用氟的独特性质在蛋白质工程领域的应用潜力非常重要。
