Soluble Zwitterionic Poly(sulfobetaine) Destabilizes Proteins

Biomacromolecules. 2018 Sep 10;19(9):3894-3901. doi: 10.1021/acs.biomac.8b01120. Epub 2018 Aug 17.


The widespread interest in neutral, water-soluble polymers such as poly(ethylene glycol) (PEG) and poly(zwitterions) such as poly(sulfobetaine) (pSB) for biomedical applications is due to their widely assumed low protein binding. Here we demonstrate that pSB chains in solution can interact with proteins directly. Moreover, pSB can reduce the thermal stability and increase the protein folding cooperativity relative to proteins in buffer or in PEG solutions. Polymer-dependent changes in the tryptophan fluorescence spectra of three structurally-distinct proteins reveal that soluble, 100 kDa pSB interacts directly with all three proteins and changes both the local polarity near tryptophan residues and the protein conformation. Thermal denaturation studies show that the protein melting temperatures decrease by as much as ∼1.9 °C per weight percent of polymer and that protein folding cooperativity increases by as much as ∼130 J mol-1 K-1 per weight percent of polymer. The exact extent of the changes is protein-dependent, as some proteins exhibit increased stability, whereas others experience decreased stability at high soluble pSB concentrations. These results suggest that pSB is not universally protein-repellent and that its efficacy in biotechnological applications will depend on the specific proteins used.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Betaine / analogs & derivatives*
  • Betaine / chemistry
  • Humans
  • NIMA-Interacting Peptidylprolyl Isomerase / chemistry*
  • Phosphoglycerate Kinase / chemistry*
  • Polyethylene Glycols / chemistry
  • Protein Folding*
  • Protein Stability
  • Repressor Proteins / chemistry*
  • Viral Regulatory and Accessory Proteins / chemistry*


  • NIMA-Interacting Peptidylprolyl Isomerase
  • Repressor Proteins
  • Viral Regulatory and Accessory Proteins
  • phage repressor proteins
  • Betaine
  • Polyethylene Glycols
  • sulfobetaine
  • Phosphoglycerate Kinase