Hidden thermodynamics of mutant proteins: A molecular dynamics analysis

Jiali Gao, Krzysztof Kuczera, Bruce Tidor, Martin Karplus

Research output: Contribution to journalArticlepeer-review

229 Scopus citations


A molecular dynamics simulation method is used to determine the contributions of individual amino acid residues and solvent molecules to free energy changes in proteins. Its application to the hemoglobin interface mutant Asp G1(99)β→Ala shows that some of the contributions to the difference in the free energy of cooperativity are as large as 60 kilocalories (kcal) per mole. Since the overall free energy change is only -5.5 kcal/mole (versus the experimental value of -3.4 kcal/mole), essential elements of the thermodynamics are hidden in the measured results. By exposing the individual contributions, the free energy simulation provides new insights into the origin of thermodynamic changes in mutant proteins and demonstrates the role of effects beyond those usually considered in structural analyses.

Original languageEnglish (US)
Pages (from-to)1069-1072
Number of pages4
Issue number4908
StatePublished - Jan 1 1989
Externally publishedYes


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