The Multiple Origins of the Hydrophobicity of Fluorinated Apolar Amino Acids

Robalo, João R.; Huhmann, Susanne; Koksch, Beate; Verde, Ana Vila

doi:10.1016/j.chempr.2017.09.012

Cited by 47 publications

(78 citation statements)

References 78 publications

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“…This observation is in good agreement with HPLC results [3b] as well as theory, [26] and indicates that the here-presented approach is sensitive to small variations within ag iven structure. Interestingly,t he fluorinated diastereomers of 4,4,4trifluorovaline yield different hydrophobicity values:T he (2S,3S)-4-F 3 -Val isomer (a = 1.061) is considerably more hydrophilic than 4-F 3 -Val(S,R)( a = 1.080), but both are more hydrophobic than Va l( a = 1.053).…”

Section: Angewandte Chemiesupporting

confidence: 91%

“…Interestingly,t he fluorinated diastereomers of 4,4,4trifluorovaline yield different hydrophobicity values:T he (2S,3S)-4-F 3 -Val isomer (a = 1.061) is considerably more hydrophilic than 4-F 3 -Val(S,R)( a = 1.080), but both are more hydrophobic than Va l( a = 1.053). This observation is in good agreement with HPLC results [3b] as well as theory, [26] and indicates that the here-presented approach is sensitive to small variations within ag iven structure.…”

Section: Angewandte Chemiesupporting

confidence: 91%

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An Intrinsic Hydrophobicity Scale for Amino Acids and Its Application to Fluorinated Compounds

et al. 2019

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More than 100 hydrophobicity scales have been introduced, with each being based on ad istinct condensedphase approach.However,acomparison of the hydrophobicity values gained from different techniques,a nd their relative ranking,isnot straightforward, as the interactions between the environment and the amino acid are unique to each method. Here,weovercome this limitation by studying the properties of amino acids in the clean-room environment of the gas phase.In the gas phase,e ntropic contributions from the hydrophobic effect are by default absent and only the polarity of the side chain dictates the self-assembly.This allows for the derivation of an ovel hydrophobicity scale,w hichi sb ased solely on the interaction between individual amino acid units within the cluster and thus more accurately reflects the intrinsic nature of as ide chain. This principle can be further applied to classify non-natural derivatives,a ss hown here for fluorinated amino acid variants.The accurate determination of the intrinsic hydrophobicity of amino acids is crucial for understanding the key aspects of biology and the application of noncanonical amino acids in the rational design of peptides and proteins.M any fundamental biological processes such as the folding, [1] stability, [2] and oligomerization [3] of proteins as well as protein-ligand interactions [4] are strongly influenced by the hydrophobic effect in solution, where the entropically unfavored solvent shell around nonpolar residues is released to the bulk water. To date,m ore than 100 hydrophobicity scales [5] have been established, with most of them being derived from condensedphase methods such as water/octanol partitioning, [6] calculations of the accessible surface area, [7] direct measurements of physical properties, [8] and chromatographic techniques. [9]

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Section: Angewandte Chemiesupporting

confidence: 91%

Section: Angewandte Chemiesupporting

confidence: 91%

An Intrinsic Hydrophobicity Scale for Amino Acids and Its Application to Fluorinated Compounds

et al. 2019

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“…Yet, these two atoms also differ in the size and stereoelectronic features and fluorine's high electronegativity and low polarizability can affect protein-ligand interactions in different ways [21]. Here, we show that fluorination, although increased Abu hydrophobicity [22] did not improve the K M value compared to Abu, indicating that fluorine cannot substitute methylene group in the context of the IleRS active site. Finally, despite efficient discrimination of Abu at the synthetic site, Abu-tRNA Ile was still rapidly hydrolyzed at the IleRS editing domain.…”

Section: Introductionmentioning

confidence: 63%

Mechanism of discrimination of isoleucyl‐tRNA synthetase against nonproteinogenic α‐aminobutyrate and its fluorinated analogues

et al. 2019

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Isoleucyl‐tRNA synthetase (IleRS) is a paradigm for understanding how specificity against smaller hydrophobic substrates evolved in both the synthetic and editing reactions. IleRS misactivates nonproteinogenic norvaline (Nva) and proteinogenic valine (Val), with a 200‐fold lower efficiency than the cognate isoleucine (Ile). Translational errors are, however, prevented by IleRS hydrolytic editing. Nva and Val are both smaller than Ile by a single methylene group. How does the removal of one additional methylene group affects IleRS specificity? We found that the nonproteinogenic α‐aminobutyrate (Abu) is activated 30‐fold less efficiently than Nva and Val, indicating that the removal of the second methylene group comes with a lower penalty. As with Nva and Val, discrimination against Abu predominantly originated from a higher KM. To examine whether increased hydrophobicity could compensate for the loss of van der Waals interactions, we tested fluorinated Abu analogues. We found that fluorination further hampered activation by IleRS, and even more so by the evolutionary‐related ValRS. This suggests that hydrophobicity is not a main driving force of substrate binding in these enzymes. Finally, a discrimination factor of 7100 suggests that IleRS is not expected to edit Abu. However, we found that the IleRS editing domain hydrolyzes Abu‐tRNAIle with a rate of 40 s−1 and the introduction of fluorine did not slow down the hydrolysis. This raises interesting questions regarding the mechanism of specificity of the editing domain and its evolution. Understanding what shapes IleRS specificity is also of importance for reengineering translation to accommodate artificial substrates including fluorinated amino acids. Enzymes Isoleucyl‐tRNA synthetase (EC 6.1.1.5), leucyl‐tRNA synthetase (EC 6.1.1.4), valyl‐tRNA synthetase (EC 6.1.1.9).

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“…Unfortunately, in the case of fluorinated unnatural amino acids the influence of the fluorine atom on the hydrophobicity is more difficult to predict . An interesting approach by which to determine hydrophobicity is through reversed‐phase (RP) HPLC .…”

Section: Introductionmentioning

confidence: 99%

Incorporating a Monofluoroalkene into the Backbones of Short Peptides: Evaluating the Impact on Local Hydrophobicity

2019

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The local hydrophobicity of an amino acid residue in a peptide sequence can be determined by measuring the hydrophobicity index (φ0) by reversed‐phase (RP) HPLC. Herein, the impact on the local hydrophobicity of the replacement of an amide by a monofluoroalkene unit in short peptides is discussed. Monofluoroalkene‐containing dipeptides and tripeptides were synthesized, as well as their natural parent compounds, and the hydrophobicity indexes of these short peptides and peptidomimetics were determined. Comparison between the natural parent peptides and their alkene‐containing analogues was made, and the dependence of the peptidomimetic analogues’ behaviour on the pH and the solvent was studied. It was found that the presence of a monofluoroalkene unit enhanced a peptide's hydrophobicity.

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The Multiple Origins of the Hydrophobicity of Fluorinated Apolar Amino Acids

Cited by 47 publications

References 78 publications

An Intrinsic Hydrophobicity Scale for Amino Acids and Its Application to Fluorinated Compounds

An Intrinsic Hydrophobicity Scale for Amino Acids and Its Application to Fluorinated Compounds

Mechanism of discrimination of isoleucyl‐tRNA synthetase against nonproteinogenic α‐aminobutyrate and its fluorinated analogues

Incorporating a Monofluoroalkene into the Backbones of Short Peptides: Evaluating the Impact on Local Hydrophobicity

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