Fluorine in Protein Environments: A QM and MD Study

Abstract

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.

Synthesis of enantiomerically pure (2S,3S)-5,5,5-trifluoroisoleucine and (2R,3S)-5,5,5-trifluoro-allo-isoleucine

“…In agreement with previous studies that focused on other fluorinated amino acids [26], also the retention times of 5-F 3 Ile and 4’-F 3 Ile do not fit into the correlation between side chain volume and retention time (Fig. 1).…”

“…By plotting their side chain van der Waals volume versus their retention time from an RP-HPLC experiment, we previously investigated the relationship between size and hydrophobicity of various fluorinated and non-fluorinated amino acids [26]. In this experiment the non-polar phase of a reversed-phase column serves as a mimic of a biological membrane or the kind of hydrophobic interactions, that would be present in hydrophobic cores of proteins and in ligand–receptor binding [27].…”

Fluorine–Protein Interactions and 19F NMR Isotropic Chemical Shifts: An Empirical Correlation with Implications for Drug Design

“…In addition to various aspects that one needs to consider upon addition of fluorine to a molecule (e.g., effect Figure 12. Plot of the F···HÀO of CH 3 CH 2 OH computed distance with HF and B3LYP (6-311G** + + ) quantum chemical methods for three different ethanes (indicated in the figure) [59] as a function of their 19 F chemical shifts. The data were fitted to mono-exponential functions of the type y = y 0 + A e (ÀBx) .…”

“…In addition, physicochemical properties of fluorinated amino acids have recently been characterized by QM and molecular dynamics approaches. [59] The geometry, charges, and hydrogen bonding abilities of several fluorinated ethane derivatives at different QM theoretical levels were analyzed and used as simplified models for fluorinated amino acid side chains. Four new fluorinated l-amino acids were parameterized, and the new parameters were added to the AMBER ff94/99 force field: 4-monofluoroethylglycine, 4,4-difluoroethylglycine, 4,4,4-trifluoroethylglycine, and 4,4-difluoropropylglycine.…”

“…Four new fluorinated l-amino acids were parameterized, and the new parameters were added to the AMBER ff94/99 force field: 4-monofluoroethylglycine, 4,4-difluoroethylglycine, 4,4,4-trifluoroethylglycine, and 4,4-difluoropropylglycine. Interestingly, the ability of fluorine to act as a hydrogen bond acceptor in various fluorinated ethane derivatives was ranked in the following order: CH 3 Figure 12, in which the F···HÀO distance of CH 3 CH 2 OH was computed for three ethanes using the quantum chemical methods Hartree-Fock (HF) and Becke 3-Parameter Lee, Yang and Parr (B3LYP) [59] with the basis set 6-311G** + + as a function of the 19 F chemical shift. Although the distances computed with the two methods are different, the overall behavior is similar.…”