The hydrophobic effect: A new insight from cold denaturation and a two-state water structure

Chung Jung Tsai*, Jacob V. Maizel, Ruth Nussinov

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review


Herein we provide a new insight into the hydrophobic effect in protein folding. Our proposition explains the molecular basis of cold denaturation, and of intermediate states in heat and their absence in cold denaturation. The exposure of non-polar surface reduces the entropy and enthalpy of the system, at low and at high temperatures. At low temperatures the favorable reduction in enthalpy overcomes the unfavorable reduction in entropy, leading to cold denaturation. At high temperatures, folding/unfolding is a two-step process: in the first, the entropy gain leads to hydrophobic collapse, in the second, the reduction in enthalpy due to protein-protein interactions leads to the native state. The different entropy and enthalpy contributions to the Gibbs energy change at each step at high, and at low, temperatures can be conveniently explained by a two-state model of the water structure. The model provides a clear view of the dominant factors in protein folding and stability. Consequently, it appears to provide a microscopic view of the hydrophobic effect and is consistently linked to macroscopic thermodynamic parameters.

Original languageEnglish
Pages (from-to)55-69
Number of pages15
JournalCritical Reviews in Biochemistry and Molecular Biology
Issue number2
StatePublished - 2002


  • Cold denaturation
  • Entropy
  • Hydrophobic effect
  • Molecular simulations
  • Molten globule
  • Water structure
  • α-lactalbumin


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