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PDBsum entry 6o2e
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Transcription
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PDB id
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6o2e
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References listed in PDB file
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Key reference
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Title
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Influence of pegylation on the strength of protein surface salt bridges.
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Authors
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Q.Xiao,
S.R.E.Draper,
M.S.Smith,
N.Brown,
N.A.B.Pugmire,
D.S.Ashton,
A.J.Carter,
E.E.K.Lawrence,
J.L.Price.
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Ref.
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ACS Chem Biol, 2019,
14,
1652-1659.
[DOI no: ]
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PubMed id
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Abstract
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Conjugation of polyethylene glycol (PEGylation) is a well-known strategy for
extending the serum half-life of protein drugs and for increasing their
resistance to proteolysis and aggregation. We previously showed that PEGylation
can increase protein conformational stability; the extent of PEG-based
stabilization depends on the PEGylation site, the structure of the PEG-protein
linker, and the ability of PEG to release water molecules from the surrounding
protein surface to the bulk solvent. The strength of a noncovalent interaction
within a protein depends strongly on its microenvironment, with salt-bridge and
hydrogen-bond strength increasing in nonpolar versus aqueous environments.
Accordingly, we wondered whether partial desolvation by PEG of the surrounding
protein surface might result in measurable increases in the strength of a salt
bridge near a PEGylation site. Here we explore this possibility using
triple-mutant box analysis to assess the impact of PEGylation on the strength of
nearby salt bridges at specific locations within three peptide model systems.
The results indicate that PEG can increase the nearby salt-bridge strength,
though this effect is not universal, and its precise structural prerequisites
are not a simple function of secondary structural context, of the orientation
and distance between the PEGylation site and salt bridge, or of salt-bridge
residue identity. We obtained high-resolution X-ray diffraction data for a
PEGylated peptide in which PEG enhances the strength of a nearby salt bridge.
Comparing the electron density map of this PEGylated peptide versus that of its
non-PEGylated counterpart provides evidence of localized protein surface
desolvation as a mechanism for PEG-based salt-bridge stabilization.
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