Conjugation of ethylene oxide oligomers (i.e., PEGylation) to nucleophilic groups on the surfaces of folded proteins can improve the storage and pharmacokinetic properties of protein drugs by lengthening serum half-life and shelf-life and decreasing protease susceptibility and aggregation. These beneficial effects could be enhanced if PEGylation consistently increased protein thermodynamic stability.  However, the energetic effects of PEGylation are currently unpredictable: PEGylation can increase, decrease, or have no effect on protein stability, and the molecular basis for this is poorly understood. Here we seek to develop clear guidelines for increasing protein stability via PEGylation. We  recently showed that PEGylation at a specific site in the WW domain of the human protein Pin 1 (WW) is energetically stabilizing. We hypothesize that this is due to an excluded-volume effect which destabilizes the unfolded protein. Herein we report the results of our investigations into the mechanism of this stabilizing effect.

Investigation into the effects of PEGylation on the thermodynamic stability of the WW domain

243rd National Meeting (2012)

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