Patterns of protein-protein interactions in salt solutions and implications for protein crystallization

André C. Dumetz, Ann M. Snellinger-O'Brien, Eric W. Kaler, Abraham M. Lenhoff

Research output: Contribution to journalArticlepeer-review

157 Scopus citations


The second osmotic virial coefficients of seven proteins - ovalbumin, ribonuclease A, bovine serum albumin, α-lactalbumin, myoglobin, cytochrome c, and catalase - were measured in salt solutions. Comparison of the interaction trends in terms of the dimensionless second virial coefficient b2 shows that, at low salt concentrations, protein-protein interactions can be either attractive or repulsive, possibly due to the anisotropy of the protein charge distribution. At high salt concentrations, the behavior depends on the salt: In sodium chloride, protein interactions generally show little salt dependence up to very high salt concentrations, whereas in ammonium sulfate, proteins show a sharp drop in b2 with increasing salt concentration beyond a particular threshold. The experimental phase behavior of the proteins corroborates these observations in that precipitation always follows the drop in b2. When the proteins crystallize, they do so at slightly lower salt concentrations than seen for precipitation. The b2 measurements were extended to other salts for ovalbumin and catalase. The trends follow the Hofmeister series, and the effect of the salt can be interpreted as a water-mediated effect between the protein and salt molecules. The b2 trends quantify protein-protein interactions and provide some understanding of the corresponding phase behavior. The results explain both why ammonium sulfate is among the best crystallization agents, as well as some of the difficulties that can be encountered in protein crystallization.

Original languageEnglish (US)
Pages (from-to)1867-1877
Number of pages11
JournalProtein Science
Issue number9
StatePublished - Sep 2007


  • Osmotic second virial coefficient
  • Protein crystallization
  • Protein interactions
  • Self-interaction chromatography


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