3TWE: Crystal Structure of the de novo designed peptide alpha4H

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.
PDB ID: 3TWEDownload
MMDB ID: 97950
PDB Deposition Date: 2011/9/21
Updated in MMDB: 2017/11
Experimental Method:
x-ray diffraction
Resolution: 1.36  Å
Similar Structures:
Biological Unit for 3TWE: tetrameric; determined by author and by software (PISA)
Molecular Components in 3TWE
Label Count Molecule
Proteins (4 molecules)
Molecule annotation
Chemicals (4 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB