Balance of enthalpy and entropy in depletion forces

Shahar Sukenik, Liel Sapir, Daniel Harries*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

81 Scopus citations


Solutes added to solutions often dramatically impact molecular processes ranging from the suspension or precipitation of colloids to biomolecular associations and protein folding. Here we revisit the origins of the effective attractive interactions that emerge between and within macromolecules immersed in solutions containing cosolutes that are preferentially excluded from the macromolecular interfaces. Until recently, these depletion forces were considered to be entropic in nature, resulting primarily from the tendency to increase the space available to the cosolute. However, recent experimental evidence indicates the existence of additional, energetically-dominated mechanisms. In this review we follow the emerging characteristics of these different mechanisms. By compiling a set of available thermodynamic data for processes ranging from protein folding to protein-protein interactions, we show that excluded cosolutes can act through two distinct mechanisms that correlate to a large extent with their molecular properties. For many polymers at low to moderate concentrations the steric interactions and molecular crowding effects dominate, and the mechanism is entropic. To contrast, for many small excluded solutes, such as naturally occurring osmolytes, the mechanism is dominated by favorable enthalpy, whereas the entropic contribution is typically unfavorable. We review the available models for these thermodynamic mechanisms, and comment on the need for new models that would be able to explain the full range of observed depletion forces.

Original languageAmerican English
Pages (from-to)495-501
Number of pages7
JournalCurrent Opinion in Colloid and Interface Science
Issue number6
StatePublished - Dec 2013

Bibliographical note

Funding Information:
Financial support from the Israel Science Foundation (ISF Grant No. 1538/13 ) is gratefully acknowledged. LS is supported by the Adams Fellowship Program of the Israel Academy of Sciences and Humanities . The Fritz Haber research center is supported by the Minerva Foundation, Munich, Germany .


  • Chemical chaperons
  • Cosolute effects
  • Depletion forces
  • Molecular crowding
  • Osmolytes
  • Preferential interaction
  • Protein folding


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