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Molecular basis of cooperativity in protein folding. V. Thermodynamic and structural conditions for the stabilization of compact denatured states.
Proteins. 1994 Aug; 19(4):291-301.P

Abstract

The heat-denatured state of proteins has been usually assumed to be a fully hydrated random coil. It is now evident that under certain solvent conditions or after chemical or genetic modifications, the protein molecule may exhibit a hydrophobic core and residual secondary structure after thermal denaturation. This state of the protein has been called the "compact denatured" or "molten globule" state. Recently is has been shown that alpha-lactalbumin at pH < 5 denatures into a molten globule state upon increasing the temperature (Griko, Y., Freire, E., Privalov, P.L. Biochemistry 33:1889-1899, 1994). This state has a lower heat capacity and a higher enthalpy at low temperatures the stabilization of the molten globule state is of an entropic origin since the enthalpy contributes unfavorably to the Gibbs free energy. Since the molten globule is more structured than the unfolded state and, therefore, is expected to have a lower configurational entropy, the net entropic gain must originate primarily from solvent related entropy arising from the hydrophobic effect, and to a lesser extent from protonation or electrostatic effects. In this work, we have examined a large ensemble of partly folded states derived from the native structure of alpha-lactalbumin in order to identify those states that satisfy the energetic criteria of the molten globule. It was found that only few states satisfied the experimental constraints and that, furthermore, those states were part of the same structural family. In particular, the regions corresponding to the A, B, and C helices were found to be folded, while the beta sheet and the D helix were found to be unfolded. At temperatures below 45 degrees C the states exhibiting those structural characteristics are enthalpically higher than the unfolded state in agreement with the experimental data. Interestingly, those states have a heat capacity close to that observed for the acid pH compact denatured state of alpha-lactalbumin [980 cal (mol.K)-1]. In addition, the folded regions of these states include those residues found to be highly protected by NMR hydrogen exchange experiments. This work represents an initial attempt to model the structural origin of the thermodynamic properties of partly folded states. The results suggest a number of structural features that are consistent with experimental data.

Authors+Show Affiliations

Department of Biology, Johns Hopkins University, Baltimore, Maryland 21218.No affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

7984625

Citation

Xie, D, and E Freire. "Molecular Basis of Cooperativity in Protein Folding. V. Thermodynamic and Structural Conditions for the Stabilization of Compact Denatured States." Proteins, vol. 19, no. 4, 1994, pp. 291-301.
Xie D, Freire E. Molecular basis of cooperativity in protein folding. V. Thermodynamic and structural conditions for the stabilization of compact denatured states. Proteins. 1994;19(4):291-301.
Xie, D., & Freire, E. (1994). Molecular basis of cooperativity in protein folding. V. Thermodynamic and structural conditions for the stabilization of compact denatured states. Proteins, 19(4), 291-301.
Xie D, Freire E. Molecular Basis of Cooperativity in Protein Folding. V. Thermodynamic and Structural Conditions for the Stabilization of Compact Denatured States. Proteins. 1994;19(4):291-301. PubMed PMID: 7984625.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Molecular basis of cooperativity in protein folding. V. Thermodynamic and structural conditions for the stabilization of compact denatured states. AU - Xie,D, AU - Freire,E, PY - 1994/8/1/pubmed PY - 1994/8/1/medline PY - 1994/8/1/entrez SP - 291 EP - 301 JF - Proteins JO - Proteins VL - 19 IS - 4 N2 - The heat-denatured state of proteins has been usually assumed to be a fully hydrated random coil. It is now evident that under certain solvent conditions or after chemical or genetic modifications, the protein molecule may exhibit a hydrophobic core and residual secondary structure after thermal denaturation. This state of the protein has been called the "compact denatured" or "molten globule" state. Recently is has been shown that alpha-lactalbumin at pH < 5 denatures into a molten globule state upon increasing the temperature (Griko, Y., Freire, E., Privalov, P.L. Biochemistry 33:1889-1899, 1994). This state has a lower heat capacity and a higher enthalpy at low temperatures the stabilization of the molten globule state is of an entropic origin since the enthalpy contributes unfavorably to the Gibbs free energy. Since the molten globule is more structured than the unfolded state and, therefore, is expected to have a lower configurational entropy, the net entropic gain must originate primarily from solvent related entropy arising from the hydrophobic effect, and to a lesser extent from protonation or electrostatic effects. In this work, we have examined a large ensemble of partly folded states derived from the native structure of alpha-lactalbumin in order to identify those states that satisfy the energetic criteria of the molten globule. It was found that only few states satisfied the experimental constraints and that, furthermore, those states were part of the same structural family. In particular, the regions corresponding to the A, B, and C helices were found to be folded, while the beta sheet and the D helix were found to be unfolded. At temperatures below 45 degrees C the states exhibiting those structural characteristics are enthalpically higher than the unfolded state in agreement with the experimental data. Interestingly, those states have a heat capacity close to that observed for the acid pH compact denatured state of alpha-lactalbumin [980 cal (mol.K)-1]. In addition, the folded regions of these states include those residues found to be highly protected by NMR hydrogen exchange experiments. This work represents an initial attempt to model the structural origin of the thermodynamic properties of partly folded states. The results suggest a number of structural features that are consistent with experimental data. SN - 0887-3585 UR - https://www.unboundmedicine.com/medline/citation/7984625/Molecular_basis_of_cooperativity_in_protein_folding__V__Thermodynamic_and_structural_conditions_for_the_stabilization_of_compact_denatured_states_ L2 - https://doi.org/10.1002/prot.340190404 DB - PRIME DP - Unbound Medicine ER -