Synthesis and thermodynamic characterization of self-sorting coiled coils

Bilgiçer, Başar; Kumar, Krishna

doi:10.1016/s0040-4020(02)00260-0

Cited by 76 publications

(81 citation statements)

References 37 publications

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“…It has been conjectured that the unusual phase-segregating properties of per-fluorinated molecules, ingeniously exploited in organic synthesis (12,14), could be used to direct protein-protein interactions in a manner orthogonal to the conventional hydrophobic effect (20)(21)(22)25); however, the structures of α 4 F 3 a and α 4 F 3 af 3 d reveal no evidence for preferential fluorous interactions between fluorinated residues.…”

Section: Discussionmentioning

confidence: 99%

“…However, evidence for such fluorous interactions in proteins seems mixed. Studies on two parallel coiled-coil systems, one soluble and one membranebound, found that incorporation of hexafluoroleucine (hFLeu) at the a and d positions of the canonical coiled-coil heptad repeat led to self-segregation of the fluorinated and nonfluorinated peptides (18,22,25). In contrast, studies in our laboratory using an antiparallel four-helix bundle system failed to find convincing evidence for fluorous self-segregation when hFLeu was, similarly, introduced at a and d positions (26,27).…”

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confidence: 82%

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Structural basis for the enhanced stability of highly fluorinated proteins

Buer¹,

Meagher

Stuckey

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Noncanonical amino acids have proved extremely useful for modifying the properties of proteins. Among them, extensively fluorinated (fluorous) amino acids seem particularly effective in increasing protein stability; however, in the absence of structural data, the basis of this stabilizing effect remains poorly understood. To address this problem, we solved X-ray structures for three small proteins with hydrophobic cores that are packed with either fluorocarbon or hydrocarbon side chains and compared their stabilities. Although larger, the fluorinated residues are accommodated within the protein with minimal structural perturbation, because they closely match the shape of the hydrocarbon side chains that they replace. Thus, stability increases seem to be better explained by increases in buried hydrophobic surface area that accompany fluorination than by specific fluorous interactions between fluorinated side chains. This finding is illustrated by the design of a highly fluorinated protein that, by compensating for the larger volume and surface area of the fluorinated side chains, exhibits similar stability to its nonfluorinated counterpart. These structure-based observations should inform efforts to rationally modulate protein function using noncanonical amino acids.de novo-designed proteins | protein structure | coiled-coil proteins | unnatural amino acids | hexafluoroleucine

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 82%

Structural basis for the enhanced stability of highly fluorinated proteins

Buer¹,

Meagher

Stuckey

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…[3] We recently reported a de novo design strategy to control oligomerization of independent transmembrane helices that relies on the unique properties of fluorinated interfaces. [4,5] These "fluorous" interfaces [6,7] self-sort from similar aliphatic protein surfaces [6,8] and also are capable of directing helix-helix interactions in the context of the nonpolar environment of detergent micelles. [9] Herein we show that coupled with hydrogen bonds as mediators of protein-protein interactions, [10] fluorinated interfaces, which are simultaneously hydrophobic and lipophobic, are superior and more efficient at directing oligomer structures in phospholipid membranes than those based on natural aliphatic side chains alone.…”

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confidence: 99%

Fluorinated Interfaces Drive Self‐Association of Transmembrane α Helices in Lipid Bilayers

Naarmann

Bilgiçer

et al. 2006

Angew Chem Int Ed

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“…In particular, we wanted to test whether preferential interactions between fluorinated residues, 15,16,34,35 sometimes referred to as the ''fluorous effect,'' were responsible for the stabilizing effects of fluorinated amino acids. This idea is predicated upon the unusual phase-segregating properties of perfluorocarbon solvents, which selectively extract highly fluorinated small molecules from organic solvents into the perfluorocarbon solvent.…”

Section: Discussionmentioning

confidence: 99%

Comparison of the structures and stabilities of coiled‐coil proteins containing hexafluoroleucine and t‐butylalanine provides insight into the stabilizing effects of highly fluorinated amino acid side‐chains

et al. 2012

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Highly fluorinated analogs of hydrophobic amino acids are well known to increase the stability of proteins toward thermal unfolding and chemical denaturation, but there is very little data on the structural consequences of fluorination. We have determined the structures and folding energies of three variants of a de novo designed 4-helix bundle protein whose hydrophobic cores contain either hexafluoroleucine (hFLeu) or t-butylalanine (tBAla). Although the buried hydrophobic surface area is the same for all three proteins, the incorporation of tBAla causes a rearrangement of the core packing, resulting in the formation of a destabilizing hydrophobic cavity at the center of the protein. In contrast, incorporation of hFLeu, causes no changes in core packing with respect to the structure of the nonfluorinated parent protein which contains only leucine in the core. These results support the idea that fluorinated residues are especially effective at stabilizing proteins because they closely mimic the shape of the natural residues they replace while increasing buried hydrophobic surface area.

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Synthesis and thermodynamic characterization of self-sorting coiled coils

Cited by 76 publications

References 37 publications

Structural basis for the enhanced stability of highly fluorinated proteins

Structural basis for the enhanced stability of highly fluorinated proteins

Fluorinated Interfaces Drive Self‐Association of Transmembrane α Helices in Lipid Bilayers

Comparison of the structures and stabilities of coiled‐coil proteins containing hexafluoroleucine and t‐butylalanine provides insight into the stabilizing effects of highly fluorinated amino acid side‐chains

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